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Papers by Marie Gibbs

Research paper thumbnail of Fluxes of lactate into, from, and among gap junction-coupled astrocytes and their interaction with noradrenaline

Frontiers in neuroscience, 2014

Lactate is a versatile metabolite with important roles in modulation of brain glucose utilization... more Lactate is a versatile metabolite with important roles in modulation of brain glucose utilization rate (CMRglc), diagnosis of brain-injured patients, redox- and receptor-mediated signaling, memory, and alteration of gene transcription. Neurons and astrocytes release and accumulate lactate using equilibrative monocarboxylate transporters that carry out net transmembrane transport of lactate only until intra- and extracellular levels reach equilibrium. Astrocytes have much faster lactate uptake than neurons and shuttle more lactate among gap junction-coupled astrocytes than to nearby neurons. Lactate diffusion within syncytia can provide precursors for oxidative metabolism and glutamate synthesis and facilitate its release from endfeet to perivascular space to stimulate blood flow. Lactate efflux from brain during activation underlies the large underestimation of CMRglc with labeled glucose and fall in CMRO2/CMRglc ratio. Receptor-mediated effects of lactate on locus coeruleus neurons...

Research paper thumbnail of Antagonists of the Vasopressin V1 Receptor and of the β(1)-Adrenoceptor Inhibit Cytotoxic Brain Edema in Stroke by Effects on Astrocytes - but the Mechanisms Differ

Current neuropharmacology, 2014

Brain edema is a serious complication in ischemic stroke because even relatively small changes in... more Brain edema is a serious complication in ischemic stroke because even relatively small changes in brain volume can compromise cerebral blood flow or result in compression of vital brain structures on account of the fixed volume of the rigid skull. Literature data indicate that administration of either antagonists of the V1 vasopressin (AVP) receptor or the β1-adrenergic receptor are able to reduce edema or infarct size when administered after the onset of ischemia, a key advantage for possible clinical use. The present review discusses possible mechanisms, focusing on the role of NKCC1, an astrocytic cotransporter of Na(+), K(+), 2Cl(-) and water and its activation by highly increased extracellular K(+) concentrations in the development of cytotoxic cell swelling. However, it also mentions that due to a 3/2 ratio between Na(+) release and K(+) uptake by the Na(+),K(+)-ATPase driving NKCC1 brain extracellular fluid can become hypertonic, which may facilitate water entry across the bl...

Research paper thumbnail of Inhibition of astrocytic energy metabolism by D-lactate exposure impairs memory

Neurochemistry international, 2008

Bead discrimination learning in day-old chicken was inhibited by bilateral injection into the int... more Bead discrimination learning in day-old chicken was inhibited by bilateral injection into the intermediate medial mesopallium (IMM), a homolog of the mammalian brain cortex, of the poorly metabolized enantiomer of L-lactate, D-lactate. The window of vulnerability extended from 10 min before training to 20 min after training. Unilateral injection 10 min before training inhibited only in the left IMM, whereas 10 min after training injection was only inhibitory if made into the right hemisphere. The pre-training administration caused memory loss from the earliest time tested whereas memory was maintained for another 20 min when D-lactate was injected 10 min post-training. The ability of acetate, an astrocyte-specific substrate, injected into the IMM to counteract the inhibitory effect was tested. Following D-lactate injection 10 min before training, rescue of memory immediately after training was achieved by acetate as long as aspartate, an oxaloacetate precursor, was also present. Thi...

Research paper thumbnail of Ultrasound exposure of the foetal chick brain: effects on learning and memory

International Journal of Developmental Neuroscience, 2009

Research paper thumbnail of Maternal hen calls modulate memory formation in the day-old chick: The role of noradretialine

Neurobiology of Learning and Memory, 2007

Facilitation of memory for discriminative learning in young chicks is enhanced following exposure... more Facilitation of memory for discriminative learning in young chicks is enhanced following exposure to a synthesized rhythmic auditory stimulus. Increased arousal, mediated by noradrenergic activation, is believed to underlie this effect. In this report we examine whether ethologically relevant rhythmic auditory stimuli produce the same noradrenaline-mediated memory enhancement in neonate chicks (Gallus gallus domesticus). Maternal hen attraction calls which contained a rhythmic pattern were found to facilitate retention. Intracerebral injection of noradrenaline or the b 2 -adrenergic antagonist propranolol demonstrated that this enhancement is likely to be mediated by noradrenergic activation of central b 2 -noradrenergic receptors. In contrast, a rhythmic alarm call inhibited retention. Subcutaneous injection of the a 1 -adrenergic antagonist prazosin revealed that this impairment may be due to higher arousal levels resulting in activation of a 1 -noradrenergic receptors. It is concluded that the maternal hen calls of domestic chickens can influence the memory ability of the offspring via noradrenaline release in the brain. The current data suggest that call meaning and rhythmicity interact to yield the appropriate levels of b 2 -adrenergic activation required to facilitate retention for a discriminative task.

Research paper thumbnail of The effect of hypoxia on the functional and structural development of the chick brain

International Journal of Developmental Neuroscience, 2010

Decreased oxygen availability during gestation is linked with altered structural development of t... more Decreased oxygen availability during gestation is linked with altered structural development of the brain and cognitive deficits after birth. Prehatch hypoxia can induce gross neuropathology such as brain lesions or more subtle injury including selective neuronal cell loss, white matter injury and gliosis. In the current study we used the developing chick embryo to determine whether 24 h of hypoxia at different prehatch ages, embryonic day 10, 12 or 14 (E10, E12 or E14), resulted in an alteration in neuronal cell number or astrocyte density in brain areas associated with learning and memory. Twenty-four hours of hypoxia (14% oxygen) commencing at E10 resulted in an increase in the density of GFAP-positive astrocytes in the medial striatum (MSt) (P < 0.05) and a significant reduction in the number of NeuN-positive neuronal nuclei in the intermediate medial mesopallium (IMM) (P < 0.02). Hypoxia at E14 resulted in an increase in GFAP immunoreactivity in the hippocampus (P ≤ 0.02) and a significant decrease in the number of NeuNpositive cells in the IMM (P < 0.04). Memory was tested soon after hatch using a bead discrimination learning task and results showed that E10 hypoxia significantly reduced short-term memory, which subsequently affected all stages of memory formation (P < 0.001), whereas 24 h of hypoxia at E14 did not alter short-term memory, but impaired consolidation into long-term memory (P < 0.02). Interestingly, 24 h of hypoxia at E12 did not alter GFAP immunoreactivity or NeuN-positive cells, nor did it result in memory deficits. We find that an alteration in the number or a disruption in the normal development of astrocytes and neurons significantly affects memory formation and consolidation in the young chick.

Research paper thumbnail of 1080: Cranial Ultrasound During Development Can Affect Learning and Memory

Ultrasound in Medicine & Biology, 2009

Objectives: Ultrasonically activated scalpel (UAS) is a surgical device utilizing ultrasonic ener... more Objectives: Ultrasonically activated scalpel (UAS) is a surgical device utilizing ultrasonic energy to cut and coagulate tissues simultaneously. It is concerned that UAS may give damage to the tissues of different position from a designed treatment part by bioeffect of ultrasound. We verified the relationship of the vibration characteristics and bioeffect of UAS by multiple observation methods. Methods: The laser Doppler vibrometer is used for the confirmation of the vibration distribution of some types of blades of UAS. Then, the observation experiment about generating of cavitations was conducted in the water tank. Additionally, the change of temperature distribution on the mesenterium tissue around the blade during activation was observed by an infrared thermography. Results: The generating direction of cavitations and the vibration distribution was in agreement in every blade. The emergence rate of bubble and sound pressure distribution were also in agreement. The cavitations occurred besides the part for medical treatment in the grasp type blade. The coagulated range of the mesentery was spread according to the time of activation, and the form of the coagulated part was approximately in agreement with vibration distribution of each blade. Conclusions: The direction of the generating of cavitations and the thermal diffusion were about in agreement with designed vibration of each blade. Although the tissue damage by cavitations was not confirmed in these case, it is required the consideration of the influence by the mixture situation of some tissues in grasped area and the angle between the blade and tissue.

Research paper thumbnail of Assessment of learning ability and behaviour in low birthweight lambs following intrauterine growth restriction

Reproduction, Fertility and Development, 2000

The present study used behavioural tasks to assess learning ability and behaviour in postnatal la... more The present study used behavioural tasks to assess learning ability and behaviour in postnatal lambs, and to examine the effects of low birthweight (LBW) and age on subsequent performance. It was hypothesized that intrauterine growth restriction (IUGR) and LBW lead to learning and behavioural deficits in the early postnatal period. IUGR and LBW were induced by umbilico-placental embolization from 120 days of gestational age (g.a.) to the onset of labour. Behavioural studies were performed on 6 LBW and 6 control lambs between 2 and 6 weeks after birth. LBW lambs were born at 139+/-1 days g.a. (2.4+/-0.2 kg) and control lambs were born at 149+/-1 days g.a. (4.5+/-0.4 kg). Three tasks were used to assess the learning ability and behaviour of the lambs: a simple maze, an obstacle course, and a T-maze. LBW lambs took longer to complete the simple maze at all ages, and made a greater number of errors at Week 1 of testing compared to control lambs; the total trial duration and number of errors decreased with age for both groups. In the obstacle course, the times taken to complete the first and third trials were used for analysis; a decrease in trial time and the number of errors from Trial 1 to Trial 3 were indications of the lamb&#39;s ability to learn how to negotiate the objects within the course. LBW lambs recorded longer trial durations for the first trial at Week 5 of testing, and for the third trial at Week 4. LBW lambs made more errors for the first trial at Week 5 of testing than control lambs. In the T-maze, there was no significant effect of treatment or age. It was concluded that differences between the groups may have been the result of LBW lambs being prematurely born. The value of these tasks in the assessment of learning ability and behaviour in young lambs is discussed.

Research paper thumbnail of Role of adrenoceptor subtypes in memory consolidation

Progress in Neurobiology, 2002

Noradrenaline release in areas within the forebrain occurs following activation of noradrenergic ... more Noradrenaline release in areas within the forebrain occurs following activation of noradrenergic cells in the locus coeruleus (LoC). Release of noradrenaline by attentional/arousal/vigilance factors appears to be essential for learning and is responsible for the consolidation of memory. Noradrenaline can activate any of nine different adrenoceptor (AR) subtypes in the brain and selectivity of action may be achieved by the spatial location and relative density of the AR subtypes, by different affinities of the different subtypes and by temporal selectivity in terms of when the different ARs are activated in the memory formation process. This review examines the use of selective agonists and antagonists to determine the roles of the AR subtypes in the one-trial discriminated avoidance learning paradigm in the chick. A model is developed that integrates noradrenergic activity in basal ganglia (lobus parolfactorius (LPO)) and association cortex (intermediate medial hyperstriatum ventrale (IMHV)) leading to the consolidation of memory 30 min after training. There is evidence that beta(2)- and beta(3)-ARs are important in the association area but require input from alpha(2)-AR stimulated activity in the basal ganglia for consolidation. On the other hand, alpha(1)-AR activation in the IMHV is inhibitory and prevents consolidation. While there is no role for beta(1)-ARs in memory consolidation, they play a role in short-term memory (STM). The use of the precocial chick has clear advantages in having a temporally discrete learning task which allows for discrimination memory and whose development can be followed at discrete intervals after learning. These studies reveal clear roles for AR subtypes in the formation and consolidation of memory in the chick, which have allowed the development of a model that can now be tested in mammalian systems.

Research paper thumbnail of Astrocytic involvement in learning and memory consolidation

Neuroscience & Biobehavioral Reviews, 2008

Astrocytes play fundamental roles in brain function, interacting with neurons and other astrocyte... more Astrocytes play fundamental roles in brain function, interacting with neurons and other astrocytes, yet their role in learning is not widely recognized. This review focuses on astrocytic involvement in memory consolidation following bead discrimination learning in day-old chick and draws parallels to mammalian learning, providing strong empirical support for the conclusion that the described neuronal-astrocytic interactions are universally valid. It identifies specific mechanisms whereby astrocytes support memory consolidation. Uptake of glucose, stimulated in astrocytes by beta(3)-noradrenergic receptor activation, provides energy by glycolytic/oxidative metabolism. Unlike neurons, astrocytes carry out net synthesis of tricarboxylic acid cycle intermediates needed for synthesis of transmitter glutamate formed by rapid degradation of glucose-derived glycogen and stimulated by beta(2)-noradrenergic receptor activation. This makes learning dependent on glycogenolysis and its stimulation by noradrenaline. Astrocytes take up most synaptically released glutamate, terminating transmitter activity and returning glutamate to neurons in a glutamate-glutamine cycle, interference with which abolishes learning. The various astrocytic activities follow a rigidly controlled time schedule, easily determined after bead discrimination learning but also detectable in other paradigms.

Research paper thumbnail of Complex Roles of Glutamate in the Gibbs—Ng Model of One-trial Aversive Learning in the New-born Chick

Neuroscience & Biobehavioral Reviews, 1997

Glutamate is the most widespread excitatory transmitter in the CNS and is probably involved in LT... more Glutamate is the most widespread excitatory transmitter in the CNS and is probably involved in LTP, a neural phenomenon which may be associated with learning and memory formation. Intracerebral injection of large amounts of glutamate between 5 min and 2.5 min after passive avoidance learning in young chicks inhibits short-term memory, which occurs between 0 and 10 min post-learning in a three-stage model of memory formation first established by Gibbs and Ng(25) [Physiol. Behav. 23:369-375; 1979]. This effect may be attributed to non-specific excitation. Blockade of glutamate uptake by L-aspartic and beta-hydroxamate also abolishes this stage of memory, provided the drug is administered within 2.5 min of learning. Interference with either production of percursors for transmitter glutamate in astrocytes or with glutamate receptors is also detrimental to memory formation, but the effects appear much later. After its release from glutamatergic neurons, glutamate is, to a large extent, accumulated into astrocytes where it is converted to glutamine, which can be returned to glutamatergic neurons and reutilized for synthesis of transmitter glutamate, and partly oxidized as a metabolic substrate. The latter process leads to a net loss of transmitter glutamate which can be compensated for by de novo synthesis of a glutamate precursor alpha-ketoglutarate (alpha KG) in astrocytes, a process which is inhibited by the astrocyte-specific toxin fluoroacetate (R. A. Swanson, personal communication). Intracerebral injection of this toxin abolishes memory during an intermediate stage of memory processing occurring between 20 and 30 min post-training (50) [Cog. Brain Res, 2:93-102; 1994]. Injection of methionine sulfoximine (MSO), a specific inhibitor of glutamine synthetase, which interferes with the re-supply of transmitter glutamate to neurons by inhibition of glutamine synthesis in astrocytes, has a similar effect. This effect of MSO is prevented by intracerebral injection of glutamate, glutamine, or a combination and alpha KG and alanine. MSO must be administered before learning, but does not interfere with acquisition since short-term memory remains intact. Administration of either the NMDA antagonist AP5, the AMPA antagonist DNQX, or the metabotropic receptor antagonist MCPF, also induces amnesia. Memory loss in each case does not occur until after 70 min post-training, during a protein synthesis-dependent long-term memory stage which begins at 60 min following learning. However, to be effective, AP5 must be administered within 60 s following learning, MCPG before 15 min post-learning, and DNQX between 15 and 25 min after learning. Together, these findings suggest that learning results in an immediate release of glutamate, followed by a secondary release of this transmitter at later stages of processing of the memory trace, and that one or both of these increases in extracellular glutamate concentration are essential for the consolidation of long-term memory. Since both fluoroacetate and MSO act exclusively on glial cells, the findings also show that neuronal-glial interactions are necessary during the establishment of memory.

Research paper thumbnail of Astrocyte-Neuron Interaction During One-trial Aversive Learning in the Neonate Chick **These results were originally presented at the Second Annual International Behavioral Neuroscience Society Conference, Clearwater Beach, Florida, USA, 22–25 April 1993

Neuroscience & Biobehavioral Reviews, 1996

During two specific stages of the Gibbs-Ng model of one-trial aversive learning in the neonate ch... more During two specific stages of the Gibbs-Ng model of one-trial aversive learning in the neonate chick, we have recently found unequivocal evidence for a crucial involvement of astrocytes. This evidence is metabolic (utilization of the astrocyte-specific energy store, glycogen, during normal learning and inhibition of memory formation by the astrocyte specific metabolic inhibitors, fluoroacetate and methionine sulfoximine) as well as physiological (abolition of memory formation in the presence of ethacrynic acid, an astrocyte-specific inhibitor of cellular reaccumulation of potassium ions). These findings are discussed in the present review in the framework of a more comprehensive description of metabolic and physiological neuronal-astrocytic interactions across an interstitial (extracellular) space bounded by minute processes from either cell type.

Research paper thumbnail of The role of catecholamines in memory impairment in chicks following reduced gas exchange in ovo

Neuroscience, 2004

We have shown previously that reducing gas exchange to chick embryos by half wrapping eggs with a... more We have shown previously that reducing gas exchange to chick embryos by half wrapping eggs with an impermeable membrane from either days 14 -18 (W14-18) or days 10 -18 (W10-18) of the 21 day incubation results in post-hatch memory deficits. In the W10-18 chicks, short-term memory following training is impaired, whereas in the W14-18 chicks, memory is intact for 30 min but does not consolidate into long-term storage. The reduction in gas exchange caused by half wrapping eggs resulted in alterations in hematocrit, O 2 and CO 2 tensions suggesting that the embryos are hypoxic and hypercapnic. Our aim was to test the hypothesis that increases in circulating levels of catecholamines in ovo, as a result of hypoxia, lead to a disturbance of the central noradrenergic pathways resulting in cognitive impairment. Noradrenaline is critical for memory consolidation and a disturbance during development could compromise cognitive ability. In the present study, plasma noradrenaline levels were significantly elevated compared with control levels 2 days after hatch in W14-18 chicks. There was also a decrease in tissue noradrenaline concentration in the anterior forebrain in both W14-18 and W10-18 chicks. The differential ability of centrally administered ␤ 2 -and ␤ 3 -adrenoceptor agonists to overcome the memory deficit post-training, suggests altered responsiveness of central ␤ 2 -adrenoceptors to noradrenaline in W14-18 chicks. By comparing the W10-18 and W14-18 chicks with those from eggs wrapped from W10-14 we show that it is the timing of the prenatal hypoxia, rather than its duration, that determines the nature of cognitive dysfunction. We conclude that prenatal hypoxia induced by restriction of gas exchange can disrupt or alter central noradrenergic transmission causing cognitive impairment.

Research paper thumbnail of Contrasting roles for β1, β2 and β3-adrenoceptors in memory formation in the chick

Neuroscience, 2005

Noradrenaline plays distinct roles in the modulation and consolidation of memory for one-trial, d... more Noradrenaline plays distinct roles in the modulation and consolidation of memory for one-trial, discriminated, avoidance learning in the chick. We have previously shown that activation of ␤ 2 -, ␤ 3 -and ␣ 1 -adrenoceptors (ARs) by injection into the multimodal forebrain association region

Research paper thumbnail of Role of β-Adrenoceptors in Memory Consolidation: β3-Adrenoceptors Act on Glucose Uptake and β2-Adrenoceptors on Glycogenolysis

Neuropsychopharmacology, 2008

Noradrenaline, acting via b 2 -and b 3 -adrenoceptors (AR), enhances memory formation in single t... more Noradrenaline, acting via b 2 -and b 3 -adrenoceptors (AR), enhances memory formation in single trial-discriminated avoidance learning in day-old chicks by mechanisms involving changes in metabolism of glucose and/or glycogen. Earlier studies of memory consolidation in chicks implicated b 3 -rather than b 2 -ARs in enhancement of memory consolidation by glucose, but did not elucidate whether stimulation of glucose uptake or of glycolysis was responsible. This study examines the role of glucose transport in memory formation using central injection of the nonselective facilitative glucose transporter (GLUT) inhibitor cytochalasin B, the endothelial/astrocytic GLUT-1 inhibitor phloretin and the Na + /energy-dependent endothelial glucose transporter (SGLT) inhibitor phlorizin. Cytochalasin B inhibited memory when injected into the mesopallium (avian cortex) either close to or between 25 and 45 min after training, whereas phloretin and phlorizin only inhibited memory at 30 min. This suggested that astrocytic/endothelial (GLUT-1) transport is critical at the time of consolidation, whereas a different transporter, probably the neuronal glucose transporter (GLUT-3), is important at the time of training. Inhibition of glucose transport by cytochalasin B, phloretin, or phlorizin also interfered with b 3 -AR-mediated memory enhancement 20 min posttraining, whereas inhibition of glycogenolysis interfered with b 2 -AR agonist enhancement of memory. We conclude that in astrocytes (1) activities of both GLUT-1 and SGLT are essential for memory consolidation 30 min posttraining; (2) neuronal GLUT-3 is essential at the time of training; and (3) b 2 -and b 3 -ARs consolidate memory by different mechanisms; b 3 -ARs stimulate central glucose transport, whereas b 2 -ARs stimulate central glycogenolysis.

Research paper thumbnail of Memory Processing in the Avian Hippocampus Involves Interactions between β-Adrenoceptors, Glutamate Receptors, and Metabolism

Neuropsychopharmacology, 2008

Noradrenaline is known to modulate memory formation in the mammalian hippocampus. We have examine... more Noradrenaline is known to modulate memory formation in the mammalian hippocampus. We have examined how noradrenaline and selective b-adrenoceptor (AR) agonists affect memory consolidation and how antagonists inhibit memory consolidation in the avian hippocampus. Injection of selective b-AR agonists and antagonists at specific times within 30 min of a weakly or strongly reinforced, single-trial, bead discrimination learning test in 1-day-old chicks allowed us to determine the pattern of b-AR involvement in hippocampal memory processing. Different b-AR subtypes were recruited in temporal sequence after learning in the order b 1 , b 3 , and b 2. We provide evidence that the effect of manipulation of b 1 -ARs by selective agonists and antagonists within 2.5 min of training parallels the action of NMDA receptor agonists and antagonists. Activation of b 3 -and b 2 -ARs facilitated memory but utilized different mechanisms: b 3 -ARs by stimulating glucose uptake and metabolism, and b 2 -ARs by increasing the breakdown of glycogenFwith both metabolic events occurring in astrocytes and affecting intermediate memory. The different receptors are activated at different times within the lifetime of labile memory and within 30 min of learning. We have defined separate roles for the three b-ARs in memory and demonstrated that the avian hippocampus is involved in learning and memory in much the same way as the hippocampus in the mammalian brain.

Research paper thumbnail of α2-adrenoceptors in the basal ganglia have a role in memory consolidation and reinforcement

Neuropharmacology, 2003

This study demonstrates a role for α 2 -adrenoceptors in the basal ganglia in the consolidation o... more This study demonstrates a role for α 2 -adrenoceptors in the basal ganglia in the consolidation of memory using weakly and strongly reinforced models of discriminated avoidance learning in the chick. The memory enhancing action of noradrenaline injected into the basal ganglia (lobus parolfactorius-LPO) was reduced in the presence of the α 2 -adrenoceptor antagonist yohimbine, but when noradrenaline was injected into the multi-modal association area (intermediate medial hyperstriatum ventrale-IMHV), yohimbine failed to prevent memory enhancement.

Research paper thumbnail of Inhibition of astrocytic energy metabolism by d-lactate exposure impairs memory

Neurochemistry International, 2008

Bead discrimination learning in day-old chicken was inhibited by bilateral injection into the int... more Bead discrimination learning in day-old chicken was inhibited by bilateral injection into the intermediate medial mesopallium (IMM), a homolog of the mammalian brain cortex, of the poorly metabolized enantiomer of L-lactate, D-lactate. The window of vulnerability extended from 10 min before training to 20 min after training. Unilateral injection 10 min before training inhibited only in the left IMM, whereas 10 min after training injection was only inhibitory if made into the right hemisphere. The pre-training administration caused memory loss from the earliest time tested whereas memory was maintained for another 20 min when D-lactate was injected 10 min post-training. The ability of acetate, an astrocytespecific substrate, injected into the IMM to counteract the inhibitory effect was tested. Following D-lactate injection 10 min before training, rescue of memory immediately after training was achieved by acetate as long as aspartate, an oxaloacetate precursor, was also present. This suggests that pyruvate carboxylation is necessary for net synthesis of glutamate, which is known to occur at this time [Gibbs, M.E., Lloyd, H.G.E., Santa, T., Hertz, L., 2007. Glycogen is a preferred glutamate precursor during learning in 1-day-old chick: biochemical and behavioral evidence. J. Neurosci. Res., 85,[3326][3327][3328][3329][3330][3331][3332][3333]. However, acetate alone rescued memory 20 min post-training (following D-lactate injection 10 min after training), indicating that pyruvate at this time is used for energy production, consistent with memory inhibition by dinitrophenol. These findings suggest that D-lactate acts by inhibiting uptake of L-lactate into astrocytes (an extracellular effect) or metabolism of pyruvate in astrocytic mitochondria (an intracellular effect). An apparent lag phase between the administration of D-lactate and its inhibition of learning favors the latter possibility. Thus, under the present experimental conditions D-lactate acts as an astrocytic metabolic inhibitor rather than as an inhibitor of neuronal L-lactate uptake, as has occasionally been suggested. Analogously, a rare reversible neurological syndrome with memory deficits, D-lactate encephalopathy, may mainly or exclusively be due to astrocytic malfunction. #

Research paper thumbnail of Behavioral and pharmacological unravelling of memory formation

Neurochemical Research, 1991

A brief description of how a passive avoidance task, using one day-old chicks, has been used to t... more A brief description of how a passive avoidance task, using one day-old chicks, has been used to test for memory formation is given. Chicks will peck at bright shiny beads but if a bead is painted with a bitter tasting chemical, after tasting it once, the chicks will refuse to peck on subsequent presentation of that bead. The chick associates the bitter taste with the particular characteristics of the bead. These experiments have led to the development of a model of memory. The basic model is made of short-term memory, which lasts 10 minutes, intermediate memory that has two phases A and B and lasts for 30 minutes and finally long-term memory. The use of certain classes of drugs to prolong, delay or abolish the various phases is described and then it is shown that many hormones and certain behavioral manipulations can modulate memory. Experiments are described which examine not only the temporal storage but delineate spatial storage within the brain. A brief discussion of current methodologies for looking at the exact spatial location of memory traces is given. The article concludes by emphasizing how even minor differences in protocols across laboratories can have large effects on the memory traces and stresses the significance Of the narrow temporal windows, around the training trial, when memory can be modulated.

Research paper thumbnail of Effects of nitric oxide inhibition on avoidance learning in the chick are lateralized and localized

Neurobiology of Learning and Memory, 2003

Bilateral administration of nitric oxide synthase inhibitors into the intermediate medial hyperst... more Bilateral administration of nitric oxide synthase inhibitors into the intermediate medial hyperstriatal (IMHV) region of the chick brain impairs memory formation for an avoidance task. The aim of the current study was to determine whether this effect was restricted to a particular location in the brain, and whether inhibition was equally effective in both hemispheres. White Leghorn  black Australorp chicks were administered 0.5 mM Nx-Nitro-L L -arginine methyl ester bilaterally into the lobus parolfactorius (LPO), or unilaterally into the IMHV. Injections into the LPO between 5 min pre-training and 40 min post-training had no effect on retention. In contrast, unilateral injections into the IMHV impaired retention and memory loss occurred from 40 min post-training. The effective administration time was hemisphere-dependent, requiring left hemisphere administration around the time of training and right hemisphere administration between 15 and 25 min post-training. These data suggest that localized nitric oxide activity in each hemisphere of the chick brain is necessary for the consolidation of memory for this task.

Research paper thumbnail of Fluxes of lactate into, from, and among gap junction-coupled astrocytes and their interaction with noradrenaline

Frontiers in neuroscience, 2014

Lactate is a versatile metabolite with important roles in modulation of brain glucose utilization... more Lactate is a versatile metabolite with important roles in modulation of brain glucose utilization rate (CMRglc), diagnosis of brain-injured patients, redox- and receptor-mediated signaling, memory, and alteration of gene transcription. Neurons and astrocytes release and accumulate lactate using equilibrative monocarboxylate transporters that carry out net transmembrane transport of lactate only until intra- and extracellular levels reach equilibrium. Astrocytes have much faster lactate uptake than neurons and shuttle more lactate among gap junction-coupled astrocytes than to nearby neurons. Lactate diffusion within syncytia can provide precursors for oxidative metabolism and glutamate synthesis and facilitate its release from endfeet to perivascular space to stimulate blood flow. Lactate efflux from brain during activation underlies the large underestimation of CMRglc with labeled glucose and fall in CMRO2/CMRglc ratio. Receptor-mediated effects of lactate on locus coeruleus neurons...

Research paper thumbnail of Antagonists of the Vasopressin V1 Receptor and of the β(1)-Adrenoceptor Inhibit Cytotoxic Brain Edema in Stroke by Effects on Astrocytes - but the Mechanisms Differ

Current neuropharmacology, 2014

Brain edema is a serious complication in ischemic stroke because even relatively small changes in... more Brain edema is a serious complication in ischemic stroke because even relatively small changes in brain volume can compromise cerebral blood flow or result in compression of vital brain structures on account of the fixed volume of the rigid skull. Literature data indicate that administration of either antagonists of the V1 vasopressin (AVP) receptor or the β1-adrenergic receptor are able to reduce edema or infarct size when administered after the onset of ischemia, a key advantage for possible clinical use. The present review discusses possible mechanisms, focusing on the role of NKCC1, an astrocytic cotransporter of Na(+), K(+), 2Cl(-) and water and its activation by highly increased extracellular K(+) concentrations in the development of cytotoxic cell swelling. However, it also mentions that due to a 3/2 ratio between Na(+) release and K(+) uptake by the Na(+),K(+)-ATPase driving NKCC1 brain extracellular fluid can become hypertonic, which may facilitate water entry across the bl...

Research paper thumbnail of Inhibition of astrocytic energy metabolism by D-lactate exposure impairs memory

Neurochemistry international, 2008

Bead discrimination learning in day-old chicken was inhibited by bilateral injection into the int... more Bead discrimination learning in day-old chicken was inhibited by bilateral injection into the intermediate medial mesopallium (IMM), a homolog of the mammalian brain cortex, of the poorly metabolized enantiomer of L-lactate, D-lactate. The window of vulnerability extended from 10 min before training to 20 min after training. Unilateral injection 10 min before training inhibited only in the left IMM, whereas 10 min after training injection was only inhibitory if made into the right hemisphere. The pre-training administration caused memory loss from the earliest time tested whereas memory was maintained for another 20 min when D-lactate was injected 10 min post-training. The ability of acetate, an astrocyte-specific substrate, injected into the IMM to counteract the inhibitory effect was tested. Following D-lactate injection 10 min before training, rescue of memory immediately after training was achieved by acetate as long as aspartate, an oxaloacetate precursor, was also present. Thi...

Research paper thumbnail of Ultrasound exposure of the foetal chick brain: effects on learning and memory

International Journal of Developmental Neuroscience, 2009

Research paper thumbnail of Maternal hen calls modulate memory formation in the day-old chick: The role of noradretialine

Neurobiology of Learning and Memory, 2007

Facilitation of memory for discriminative learning in young chicks is enhanced following exposure... more Facilitation of memory for discriminative learning in young chicks is enhanced following exposure to a synthesized rhythmic auditory stimulus. Increased arousal, mediated by noradrenergic activation, is believed to underlie this effect. In this report we examine whether ethologically relevant rhythmic auditory stimuli produce the same noradrenaline-mediated memory enhancement in neonate chicks (Gallus gallus domesticus). Maternal hen attraction calls which contained a rhythmic pattern were found to facilitate retention. Intracerebral injection of noradrenaline or the b 2 -adrenergic antagonist propranolol demonstrated that this enhancement is likely to be mediated by noradrenergic activation of central b 2 -noradrenergic receptors. In contrast, a rhythmic alarm call inhibited retention. Subcutaneous injection of the a 1 -adrenergic antagonist prazosin revealed that this impairment may be due to higher arousal levels resulting in activation of a 1 -noradrenergic receptors. It is concluded that the maternal hen calls of domestic chickens can influence the memory ability of the offspring via noradrenaline release in the brain. The current data suggest that call meaning and rhythmicity interact to yield the appropriate levels of b 2 -adrenergic activation required to facilitate retention for a discriminative task.

Research paper thumbnail of The effect of hypoxia on the functional and structural development of the chick brain

International Journal of Developmental Neuroscience, 2010

Decreased oxygen availability during gestation is linked with altered structural development of t... more Decreased oxygen availability during gestation is linked with altered structural development of the brain and cognitive deficits after birth. Prehatch hypoxia can induce gross neuropathology such as brain lesions or more subtle injury including selective neuronal cell loss, white matter injury and gliosis. In the current study we used the developing chick embryo to determine whether 24 h of hypoxia at different prehatch ages, embryonic day 10, 12 or 14 (E10, E12 or E14), resulted in an alteration in neuronal cell number or astrocyte density in brain areas associated with learning and memory. Twenty-four hours of hypoxia (14% oxygen) commencing at E10 resulted in an increase in the density of GFAP-positive astrocytes in the medial striatum (MSt) (P < 0.05) and a significant reduction in the number of NeuN-positive neuronal nuclei in the intermediate medial mesopallium (IMM) (P < 0.02). Hypoxia at E14 resulted in an increase in GFAP immunoreactivity in the hippocampus (P ≤ 0.02) and a significant decrease in the number of NeuNpositive cells in the IMM (P < 0.04). Memory was tested soon after hatch using a bead discrimination learning task and results showed that E10 hypoxia significantly reduced short-term memory, which subsequently affected all stages of memory formation (P < 0.001), whereas 24 h of hypoxia at E14 did not alter short-term memory, but impaired consolidation into long-term memory (P < 0.02). Interestingly, 24 h of hypoxia at E12 did not alter GFAP immunoreactivity or NeuN-positive cells, nor did it result in memory deficits. We find that an alteration in the number or a disruption in the normal development of astrocytes and neurons significantly affects memory formation and consolidation in the young chick.

Research paper thumbnail of 1080: Cranial Ultrasound During Development Can Affect Learning and Memory

Ultrasound in Medicine & Biology, 2009

Objectives: Ultrasonically activated scalpel (UAS) is a surgical device utilizing ultrasonic ener... more Objectives: Ultrasonically activated scalpel (UAS) is a surgical device utilizing ultrasonic energy to cut and coagulate tissues simultaneously. It is concerned that UAS may give damage to the tissues of different position from a designed treatment part by bioeffect of ultrasound. We verified the relationship of the vibration characteristics and bioeffect of UAS by multiple observation methods. Methods: The laser Doppler vibrometer is used for the confirmation of the vibration distribution of some types of blades of UAS. Then, the observation experiment about generating of cavitations was conducted in the water tank. Additionally, the change of temperature distribution on the mesenterium tissue around the blade during activation was observed by an infrared thermography. Results: The generating direction of cavitations and the vibration distribution was in agreement in every blade. The emergence rate of bubble and sound pressure distribution were also in agreement. The cavitations occurred besides the part for medical treatment in the grasp type blade. The coagulated range of the mesentery was spread according to the time of activation, and the form of the coagulated part was approximately in agreement with vibration distribution of each blade. Conclusions: The direction of the generating of cavitations and the thermal diffusion were about in agreement with designed vibration of each blade. Although the tissue damage by cavitations was not confirmed in these case, it is required the consideration of the influence by the mixture situation of some tissues in grasped area and the angle between the blade and tissue.

Research paper thumbnail of Assessment of learning ability and behaviour in low birthweight lambs following intrauterine growth restriction

Reproduction, Fertility and Development, 2000

The present study used behavioural tasks to assess learning ability and behaviour in postnatal la... more The present study used behavioural tasks to assess learning ability and behaviour in postnatal lambs, and to examine the effects of low birthweight (LBW) and age on subsequent performance. It was hypothesized that intrauterine growth restriction (IUGR) and LBW lead to learning and behavioural deficits in the early postnatal period. IUGR and LBW were induced by umbilico-placental embolization from 120 days of gestational age (g.a.) to the onset of labour. Behavioural studies were performed on 6 LBW and 6 control lambs between 2 and 6 weeks after birth. LBW lambs were born at 139+/-1 days g.a. (2.4+/-0.2 kg) and control lambs were born at 149+/-1 days g.a. (4.5+/-0.4 kg). Three tasks were used to assess the learning ability and behaviour of the lambs: a simple maze, an obstacle course, and a T-maze. LBW lambs took longer to complete the simple maze at all ages, and made a greater number of errors at Week 1 of testing compared to control lambs; the total trial duration and number of errors decreased with age for both groups. In the obstacle course, the times taken to complete the first and third trials were used for analysis; a decrease in trial time and the number of errors from Trial 1 to Trial 3 were indications of the lamb&#39;s ability to learn how to negotiate the objects within the course. LBW lambs recorded longer trial durations for the first trial at Week 5 of testing, and for the third trial at Week 4. LBW lambs made more errors for the first trial at Week 5 of testing than control lambs. In the T-maze, there was no significant effect of treatment or age. It was concluded that differences between the groups may have been the result of LBW lambs being prematurely born. The value of these tasks in the assessment of learning ability and behaviour in young lambs is discussed.

Research paper thumbnail of Role of adrenoceptor subtypes in memory consolidation

Progress in Neurobiology, 2002

Noradrenaline release in areas within the forebrain occurs following activation of noradrenergic ... more Noradrenaline release in areas within the forebrain occurs following activation of noradrenergic cells in the locus coeruleus (LoC). Release of noradrenaline by attentional/arousal/vigilance factors appears to be essential for learning and is responsible for the consolidation of memory. Noradrenaline can activate any of nine different adrenoceptor (AR) subtypes in the brain and selectivity of action may be achieved by the spatial location and relative density of the AR subtypes, by different affinities of the different subtypes and by temporal selectivity in terms of when the different ARs are activated in the memory formation process. This review examines the use of selective agonists and antagonists to determine the roles of the AR subtypes in the one-trial discriminated avoidance learning paradigm in the chick. A model is developed that integrates noradrenergic activity in basal ganglia (lobus parolfactorius (LPO)) and association cortex (intermediate medial hyperstriatum ventrale (IMHV)) leading to the consolidation of memory 30 min after training. There is evidence that beta(2)- and beta(3)-ARs are important in the association area but require input from alpha(2)-AR stimulated activity in the basal ganglia for consolidation. On the other hand, alpha(1)-AR activation in the IMHV is inhibitory and prevents consolidation. While there is no role for beta(1)-ARs in memory consolidation, they play a role in short-term memory (STM). The use of the precocial chick has clear advantages in having a temporally discrete learning task which allows for discrimination memory and whose development can be followed at discrete intervals after learning. These studies reveal clear roles for AR subtypes in the formation and consolidation of memory in the chick, which have allowed the development of a model that can now be tested in mammalian systems.

Research paper thumbnail of Astrocytic involvement in learning and memory consolidation

Neuroscience & Biobehavioral Reviews, 2008

Astrocytes play fundamental roles in brain function, interacting with neurons and other astrocyte... more Astrocytes play fundamental roles in brain function, interacting with neurons and other astrocytes, yet their role in learning is not widely recognized. This review focuses on astrocytic involvement in memory consolidation following bead discrimination learning in day-old chick and draws parallels to mammalian learning, providing strong empirical support for the conclusion that the described neuronal-astrocytic interactions are universally valid. It identifies specific mechanisms whereby astrocytes support memory consolidation. Uptake of glucose, stimulated in astrocytes by beta(3)-noradrenergic receptor activation, provides energy by glycolytic/oxidative metabolism. Unlike neurons, astrocytes carry out net synthesis of tricarboxylic acid cycle intermediates needed for synthesis of transmitter glutamate formed by rapid degradation of glucose-derived glycogen and stimulated by beta(2)-noradrenergic receptor activation. This makes learning dependent on glycogenolysis and its stimulation by noradrenaline. Astrocytes take up most synaptically released glutamate, terminating transmitter activity and returning glutamate to neurons in a glutamate-glutamine cycle, interference with which abolishes learning. The various astrocytic activities follow a rigidly controlled time schedule, easily determined after bead discrimination learning but also detectable in other paradigms.

Research paper thumbnail of Complex Roles of Glutamate in the Gibbs—Ng Model of One-trial Aversive Learning in the New-born Chick

Neuroscience & Biobehavioral Reviews, 1997

Glutamate is the most widespread excitatory transmitter in the CNS and is probably involved in LT... more Glutamate is the most widespread excitatory transmitter in the CNS and is probably involved in LTP, a neural phenomenon which may be associated with learning and memory formation. Intracerebral injection of large amounts of glutamate between 5 min and 2.5 min after passive avoidance learning in young chicks inhibits short-term memory, which occurs between 0 and 10 min post-learning in a three-stage model of memory formation first established by Gibbs and Ng(25) [Physiol. Behav. 23:369-375; 1979]. This effect may be attributed to non-specific excitation. Blockade of glutamate uptake by L-aspartic and beta-hydroxamate also abolishes this stage of memory, provided the drug is administered within 2.5 min of learning. Interference with either production of percursors for transmitter glutamate in astrocytes or with glutamate receptors is also detrimental to memory formation, but the effects appear much later. After its release from glutamatergic neurons, glutamate is, to a large extent, accumulated into astrocytes where it is converted to glutamine, which can be returned to glutamatergic neurons and reutilized for synthesis of transmitter glutamate, and partly oxidized as a metabolic substrate. The latter process leads to a net loss of transmitter glutamate which can be compensated for by de novo synthesis of a glutamate precursor alpha-ketoglutarate (alpha KG) in astrocytes, a process which is inhibited by the astrocyte-specific toxin fluoroacetate (R. A. Swanson, personal communication). Intracerebral injection of this toxin abolishes memory during an intermediate stage of memory processing occurring between 20 and 30 min post-training (50) [Cog. Brain Res, 2:93-102; 1994]. Injection of methionine sulfoximine (MSO), a specific inhibitor of glutamine synthetase, which interferes with the re-supply of transmitter glutamate to neurons by inhibition of glutamine synthesis in astrocytes, has a similar effect. This effect of MSO is prevented by intracerebral injection of glutamate, glutamine, or a combination and alpha KG and alanine. MSO must be administered before learning, but does not interfere with acquisition since short-term memory remains intact. Administration of either the NMDA antagonist AP5, the AMPA antagonist DNQX, or the metabotropic receptor antagonist MCPF, also induces amnesia. Memory loss in each case does not occur until after 70 min post-training, during a protein synthesis-dependent long-term memory stage which begins at 60 min following learning. However, to be effective, AP5 must be administered within 60 s following learning, MCPG before 15 min post-learning, and DNQX between 15 and 25 min after learning. Together, these findings suggest that learning results in an immediate release of glutamate, followed by a secondary release of this transmitter at later stages of processing of the memory trace, and that one or both of these increases in extracellular glutamate concentration are essential for the consolidation of long-term memory. Since both fluoroacetate and MSO act exclusively on glial cells, the findings also show that neuronal-glial interactions are necessary during the establishment of memory.

Research paper thumbnail of Astrocyte-Neuron Interaction During One-trial Aversive Learning in the Neonate Chick **These results were originally presented at the Second Annual International Behavioral Neuroscience Society Conference, Clearwater Beach, Florida, USA, 22–25 April 1993

Neuroscience & Biobehavioral Reviews, 1996

During two specific stages of the Gibbs-Ng model of one-trial aversive learning in the neonate ch... more During two specific stages of the Gibbs-Ng model of one-trial aversive learning in the neonate chick, we have recently found unequivocal evidence for a crucial involvement of astrocytes. This evidence is metabolic (utilization of the astrocyte-specific energy store, glycogen, during normal learning and inhibition of memory formation by the astrocyte specific metabolic inhibitors, fluoroacetate and methionine sulfoximine) as well as physiological (abolition of memory formation in the presence of ethacrynic acid, an astrocyte-specific inhibitor of cellular reaccumulation of potassium ions). These findings are discussed in the present review in the framework of a more comprehensive description of metabolic and physiological neuronal-astrocytic interactions across an interstitial (extracellular) space bounded by minute processes from either cell type.

Research paper thumbnail of The role of catecholamines in memory impairment in chicks following reduced gas exchange in ovo

Neuroscience, 2004

We have shown previously that reducing gas exchange to chick embryos by half wrapping eggs with a... more We have shown previously that reducing gas exchange to chick embryos by half wrapping eggs with an impermeable membrane from either days 14 -18 (W14-18) or days 10 -18 (W10-18) of the 21 day incubation results in post-hatch memory deficits. In the W10-18 chicks, short-term memory following training is impaired, whereas in the W14-18 chicks, memory is intact for 30 min but does not consolidate into long-term storage. The reduction in gas exchange caused by half wrapping eggs resulted in alterations in hematocrit, O 2 and CO 2 tensions suggesting that the embryos are hypoxic and hypercapnic. Our aim was to test the hypothesis that increases in circulating levels of catecholamines in ovo, as a result of hypoxia, lead to a disturbance of the central noradrenergic pathways resulting in cognitive impairment. Noradrenaline is critical for memory consolidation and a disturbance during development could compromise cognitive ability. In the present study, plasma noradrenaline levels were significantly elevated compared with control levels 2 days after hatch in W14-18 chicks. There was also a decrease in tissue noradrenaline concentration in the anterior forebrain in both W14-18 and W10-18 chicks. The differential ability of centrally administered ␤ 2 -and ␤ 3 -adrenoceptor agonists to overcome the memory deficit post-training, suggests altered responsiveness of central ␤ 2 -adrenoceptors to noradrenaline in W14-18 chicks. By comparing the W10-18 and W14-18 chicks with those from eggs wrapped from W10-14 we show that it is the timing of the prenatal hypoxia, rather than its duration, that determines the nature of cognitive dysfunction. We conclude that prenatal hypoxia induced by restriction of gas exchange can disrupt or alter central noradrenergic transmission causing cognitive impairment.

Research paper thumbnail of Contrasting roles for β1, β2 and β3-adrenoceptors in memory formation in the chick

Neuroscience, 2005

Noradrenaline plays distinct roles in the modulation and consolidation of memory for one-trial, d... more Noradrenaline plays distinct roles in the modulation and consolidation of memory for one-trial, discriminated, avoidance learning in the chick. We have previously shown that activation of ␤ 2 -, ␤ 3 -and ␣ 1 -adrenoceptors (ARs) by injection into the multimodal forebrain association region

Research paper thumbnail of Role of β-Adrenoceptors in Memory Consolidation: β3-Adrenoceptors Act on Glucose Uptake and β2-Adrenoceptors on Glycogenolysis

Neuropsychopharmacology, 2008

Noradrenaline, acting via b 2 -and b 3 -adrenoceptors (AR), enhances memory formation in single t... more Noradrenaline, acting via b 2 -and b 3 -adrenoceptors (AR), enhances memory formation in single trial-discriminated avoidance learning in day-old chicks by mechanisms involving changes in metabolism of glucose and/or glycogen. Earlier studies of memory consolidation in chicks implicated b 3 -rather than b 2 -ARs in enhancement of memory consolidation by glucose, but did not elucidate whether stimulation of glucose uptake or of glycolysis was responsible. This study examines the role of glucose transport in memory formation using central injection of the nonselective facilitative glucose transporter (GLUT) inhibitor cytochalasin B, the endothelial/astrocytic GLUT-1 inhibitor phloretin and the Na + /energy-dependent endothelial glucose transporter (SGLT) inhibitor phlorizin. Cytochalasin B inhibited memory when injected into the mesopallium (avian cortex) either close to or between 25 and 45 min after training, whereas phloretin and phlorizin only inhibited memory at 30 min. This suggested that astrocytic/endothelial (GLUT-1) transport is critical at the time of consolidation, whereas a different transporter, probably the neuronal glucose transporter (GLUT-3), is important at the time of training. Inhibition of glucose transport by cytochalasin B, phloretin, or phlorizin also interfered with b 3 -AR-mediated memory enhancement 20 min posttraining, whereas inhibition of glycogenolysis interfered with b 2 -AR agonist enhancement of memory. We conclude that in astrocytes (1) activities of both GLUT-1 and SGLT are essential for memory consolidation 30 min posttraining; (2) neuronal GLUT-3 is essential at the time of training; and (3) b 2 -and b 3 -ARs consolidate memory by different mechanisms; b 3 -ARs stimulate central glucose transport, whereas b 2 -ARs stimulate central glycogenolysis.

Research paper thumbnail of Memory Processing in the Avian Hippocampus Involves Interactions between β-Adrenoceptors, Glutamate Receptors, and Metabolism

Neuropsychopharmacology, 2008

Noradrenaline is known to modulate memory formation in the mammalian hippocampus. We have examine... more Noradrenaline is known to modulate memory formation in the mammalian hippocampus. We have examined how noradrenaline and selective b-adrenoceptor (AR) agonists affect memory consolidation and how antagonists inhibit memory consolidation in the avian hippocampus. Injection of selective b-AR agonists and antagonists at specific times within 30 min of a weakly or strongly reinforced, single-trial, bead discrimination learning test in 1-day-old chicks allowed us to determine the pattern of b-AR involvement in hippocampal memory processing. Different b-AR subtypes were recruited in temporal sequence after learning in the order b 1 , b 3 , and b 2. We provide evidence that the effect of manipulation of b 1 -ARs by selective agonists and antagonists within 2.5 min of training parallels the action of NMDA receptor agonists and antagonists. Activation of b 3 -and b 2 -ARs facilitated memory but utilized different mechanisms: b 3 -ARs by stimulating glucose uptake and metabolism, and b 2 -ARs by increasing the breakdown of glycogenFwith both metabolic events occurring in astrocytes and affecting intermediate memory. The different receptors are activated at different times within the lifetime of labile memory and within 30 min of learning. We have defined separate roles for the three b-ARs in memory and demonstrated that the avian hippocampus is involved in learning and memory in much the same way as the hippocampus in the mammalian brain.

Research paper thumbnail of α2-adrenoceptors in the basal ganglia have a role in memory consolidation and reinforcement

Neuropharmacology, 2003

This study demonstrates a role for α 2 -adrenoceptors in the basal ganglia in the consolidation o... more This study demonstrates a role for α 2 -adrenoceptors in the basal ganglia in the consolidation of memory using weakly and strongly reinforced models of discriminated avoidance learning in the chick. The memory enhancing action of noradrenaline injected into the basal ganglia (lobus parolfactorius-LPO) was reduced in the presence of the α 2 -adrenoceptor antagonist yohimbine, but when noradrenaline was injected into the multi-modal association area (intermediate medial hyperstriatum ventrale-IMHV), yohimbine failed to prevent memory enhancement.

Research paper thumbnail of Inhibition of astrocytic energy metabolism by d-lactate exposure impairs memory

Neurochemistry International, 2008

Bead discrimination learning in day-old chicken was inhibited by bilateral injection into the int... more Bead discrimination learning in day-old chicken was inhibited by bilateral injection into the intermediate medial mesopallium (IMM), a homolog of the mammalian brain cortex, of the poorly metabolized enantiomer of L-lactate, D-lactate. The window of vulnerability extended from 10 min before training to 20 min after training. Unilateral injection 10 min before training inhibited only in the left IMM, whereas 10 min after training injection was only inhibitory if made into the right hemisphere. The pre-training administration caused memory loss from the earliest time tested whereas memory was maintained for another 20 min when D-lactate was injected 10 min post-training. The ability of acetate, an astrocytespecific substrate, injected into the IMM to counteract the inhibitory effect was tested. Following D-lactate injection 10 min before training, rescue of memory immediately after training was achieved by acetate as long as aspartate, an oxaloacetate precursor, was also present. This suggests that pyruvate carboxylation is necessary for net synthesis of glutamate, which is known to occur at this time [Gibbs, M.E., Lloyd, H.G.E., Santa, T., Hertz, L., 2007. Glycogen is a preferred glutamate precursor during learning in 1-day-old chick: biochemical and behavioral evidence. J. Neurosci. Res., 85,[3326][3327][3328][3329][3330][3331][3332][3333]. However, acetate alone rescued memory 20 min post-training (following D-lactate injection 10 min after training), indicating that pyruvate at this time is used for energy production, consistent with memory inhibition by dinitrophenol. These findings suggest that D-lactate acts by inhibiting uptake of L-lactate into astrocytes (an extracellular effect) or metabolism of pyruvate in astrocytic mitochondria (an intracellular effect). An apparent lag phase between the administration of D-lactate and its inhibition of learning favors the latter possibility. Thus, under the present experimental conditions D-lactate acts as an astrocytic metabolic inhibitor rather than as an inhibitor of neuronal L-lactate uptake, as has occasionally been suggested. Analogously, a rare reversible neurological syndrome with memory deficits, D-lactate encephalopathy, may mainly or exclusively be due to astrocytic malfunction. #

Research paper thumbnail of Behavioral and pharmacological unravelling of memory formation

Neurochemical Research, 1991

A brief description of how a passive avoidance task, using one day-old chicks, has been used to t... more A brief description of how a passive avoidance task, using one day-old chicks, has been used to test for memory formation is given. Chicks will peck at bright shiny beads but if a bead is painted with a bitter tasting chemical, after tasting it once, the chicks will refuse to peck on subsequent presentation of that bead. The chick associates the bitter taste with the particular characteristics of the bead. These experiments have led to the development of a model of memory. The basic model is made of short-term memory, which lasts 10 minutes, intermediate memory that has two phases A and B and lasts for 30 minutes and finally long-term memory. The use of certain classes of drugs to prolong, delay or abolish the various phases is described and then it is shown that many hormones and certain behavioral manipulations can modulate memory. Experiments are described which examine not only the temporal storage but delineate spatial storage within the brain. A brief discussion of current methodologies for looking at the exact spatial location of memory traces is given. The article concludes by emphasizing how even minor differences in protocols across laboratories can have large effects on the memory traces and stresses the significance Of the narrow temporal windows, around the training trial, when memory can be modulated.

Research paper thumbnail of Effects of nitric oxide inhibition on avoidance learning in the chick are lateralized and localized

Neurobiology of Learning and Memory, 2003

Bilateral administration of nitric oxide synthase inhibitors into the intermediate medial hyperst... more Bilateral administration of nitric oxide synthase inhibitors into the intermediate medial hyperstriatal (IMHV) region of the chick brain impairs memory formation for an avoidance task. The aim of the current study was to determine whether this effect was restricted to a particular location in the brain, and whether inhibition was equally effective in both hemispheres. White Leghorn  black Australorp chicks were administered 0.5 mM Nx-Nitro-L L -arginine methyl ester bilaterally into the lobus parolfactorius (LPO), or unilaterally into the IMHV. Injections into the LPO between 5 min pre-training and 40 min post-training had no effect on retention. In contrast, unilateral injections into the IMHV impaired retention and memory loss occurred from 40 min post-training. The effective administration time was hemisphere-dependent, requiring left hemisphere administration around the time of training and right hemisphere administration between 15 and 25 min post-training. These data suggest that localized nitric oxide activity in each hemisphere of the chick brain is necessary for the consolidation of memory for this task.