Jaylyn Waddell - Academia.edu (original) (raw)

Papers by Jaylyn Waddell

Experimental Neurology, 2015

Hypoxia-ischemia (HI) of the brain in near-term and term infants is a leading cause of infant mor... more Hypoxia-ischemia (HI) of the brain in near-term and term infants is a leading cause of infant mortality and lifelong disability but current therapeutic approaches remain limited. Males consistently display greater vulnerability to the deleterious consequences of HI in both humans and animal models. Neurogenesis increases after neonatal HI and offers a potential therapeutic target for recovery. The steroid hormone estradiol has been extensively explored as a neuroprotectant in adult models of stroke but with mixed results. Less consideration has been afforded to this naturally occurring agent in the developing brain, which has unique challenges from the adult. Using a model of term HI in the rat we have explored the impact of this insult on cell genesis in the hippocampus of males and females and the ability of estradiol treatment immediately after insult to restore function. Both short-term (3days) and long-term (7days) post-injury were assessed and revealed that only females had markedly increased cell genesis on the short-term but both sexes were increased long-term. A battery of behavioral tests revealed motor impairment in males and compromised episodic memory while both sexes were modestly impaired in spatial memory. Juvenile social play was also depressed in both sexes after HI. Estradiol therapy improved behavioral performance in both sexes but did not reverse a deficit in hippocampal volume ipsilateral to the insult. Thus the effects of estradiol do not appear to be via cell death or proliferation but rather involve other components of neural functioning.

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 14, 2008

The basolateral nucleus of the amygdala (BLA) has been implicated in the modulation of learning a... more The basolateral nucleus of the amygdala (BLA) has been implicated in the modulation of learning after stress. Acute inescapable stress enhances classical eyeblink conditioning in male rats, whereas the same stressor impairs eyeblink conditioning in female rats. The experiments here directly assessed whether inactivation of the BLA during stress exposure would block both the stress-induced facilitation in males and the retardation of eyeblink conditioning in females. To this end, the BLA was temporarily inactivated by infusion of the GABA agonist muscimol before acute stressor exposure. All rats were trained in a different context 24 h later. Males infused with muscimol before the stressful event did not exhibit facilitated eyeblink conditioning, whereas those infused with the vehicle emitted more conditioned responses than unstressed males. Females infused with muscimol before stress did not express a deficit in conditioning, whereas those infused with vehicle and stressed emitted f...

Current Topics in Behavioral Neurosciences, 2010

Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, Jan 2, 2014

This study evaluated the longitudinal metabolic alterations after neonatal hypoxia-ischemia (HI) ... more This study evaluated the longitudinal metabolic alterations after neonatal hypoxia-ischemia (HI) in rats and tested the neuroprotective effect of acetyl-L-carnitine (ALCAR) using in vivo proton short-TE Point-RESolved Spectroscopy method. Rice-Vannucci model was used on 7-day-old Sprague-Dawley rats. Data were acquired from contralateral and ipsilateral cortex and hippocampus, respectively at 4 time points (24-h, 72-h, 7-days, 28-days) post-HI. The effect of subcutaneous administration of ALCAR (100 mg/kg) immediately after HI, at 4-h, 24-h, and 48-h post-HI was determined. Significant reductions in glutathione (P < 0.005), myo-inositol (P < 0.002), taurine (P < 0.001), and total creatine (P < 0.005) were observed at 24-h postinjury compared with the control group in the ipsilateral hippocampus of the HI rat pups. ALCAR-treated-HI rats had lower levels of lactate and maintained total creatine at 24-h and had smaller lesion size compared with the HI only rats. Severe oxid...

Journal of Neuroscience, 2010

Acute stress exposure enhances classical eyeblink conditioning in male rats, whereas exposure to ... more Acute stress exposure enhances classical eyeblink conditioning in male rats, whereas exposure to the same event dramatically impairs performance in females . We hypothesized that stress affects learning differently in males and females because different brain regions and circuits are being activated. In the first experiment, we determined that neuronal activity within the medial prefrontal cortex (mPFC) during the stressful event is necessary to disrupt learning in females. In both males and females, the mPFC was bilaterally inactivated with GABA agonist muscimol prior to the stressor. Inactivation prevented only the impaired performance in females; it had no consequence for performance in males. However, in the second experiment, excitation of the mPFC alone with GABA antagonist picrotoxin appeared insufficient to elicit the stress effect that was prevented through the inactivation of this region in females. Therefore, we hypothesized that the mPFC communicates with the BLA to disrupt learning in females after the stressor. To test this hypothesis, these structures were disconnected from each other with unilateral excitotoxic (NMDA) lesions on either the same or opposite sides of the brain. Females with contralateral lesions, which disrupt the connections on both sides of the brain, were able to learn after the stressful event, whereas those with ipsilateral lesions, which disrupt only one connection, did not learn after the stressor. Together, these data indicate that the mPFC is critically involved in females during stress to impair subsequent learning and does so via communication with the amygdala.

Journal of Neuroscience, 2006

Some, but not all, types of learning and memory can influence neurogenesis in the adult hippocamp... more Some, but not all, types of learning and memory can influence neurogenesis in the adult hippocampus. Trace eyeblink conditioning has been shown to enhance the survival of new neurons, whereas delay eyeblink conditioning has no such effect. The key difference between the two training procedures is that the conditioning stimuli are separated in time during trace but not delay conditioning. These findings raise the question of whether temporal discontiguity is necessary for enhancing the survival of new neurons. Here we used two approaches to test this hypothesis. First, we examined the influence of a delay conditioning task in which the duration of the conditioned stimulus (CS) was increased nearly twofold, a procedure that critically engages the hippocampus. Although the CS and unconditioned stimulus are contiguous, this very long delay conditioning procedure increased the number of new neurons that survived. Second, we examined the influence of learning the trace conditioned response (CR) after having acquired the CR during delay conditioning, a procedure that renders trace conditioning hippocampalindependent. In this case, trace conditioning did not enhance the survival of new neurons. Together, these results demonstrate that associative learning increases the survival of new neurons in the adult hippocampus, regardless of temporal contiguity.

PLoS ONE, 2011

Two recent reports propose that the depolarizing action of GABA in the immature brain is an artif... more Two recent reports propose that the depolarizing action of GABA in the immature brain is an artifact of in vitro preparations in which glucose is the only energy source. The authors argue that this does not mimic the physiological environment because the suckling rats use ketone bodies and pyruvate as major sources of metabolic energy. Here, we show that availability of physiologically relevant levels of ketone bodies has no impact on the excitatory action of GABA in immature cultured hippocampal neurons. Addition of b-hydroxybutyrate (BHB), the primary ketone body in the neonate rat, affected neither intracellular calcium elevation nor membrane depolarizations induced by the GABA-A receptor agonist muscimol, when assessed with calcium imaging or perforated patch-clamp recording, respectively. These results confirm that the addition of ketone bodies to the extracellular environment to mimic conditions in the neonatal brain does not reverse the chloride gradient and therefore render GABA hyperpolarizing. Our data are consistent with the existence of a genuine ''developmental switch'' mechanism in which GABA goes from having a predominantly excitatory role in immature cells to a predominantly inhibitory one in adults.

Neurobiology of Learning and Memory, 2011

Trace eyeblink conditioning in which a conditioned stimulus and unconditioned stimulus are separa... more Trace eyeblink conditioning in which a conditioned stimulus and unconditioned stimulus are separated by a gap, is hippocampal dependent and can rescue new neurons in the adult dentate gyrus from death (e.g., . Tasks requiring more training trials for reliable expression of the conditioned response are most effective in enhancing survival of neurons . To dissociate hippocampal dependence from acquisition rate, we facilitated hippocampal-dependent trace eyeblink conditioning in two ways: a shorter trace interval and signaling the intertrial interval with a post-US cue. Trace conditioning with a shorter trace interval (250 ms) requires an intact hippocampus, and acquisition is faster relative to rats trained with a 500 ms trace interval (e.g., . Using excitotoxic hippocampal lesions, we confirmed that eyeblink conditioning with the 250 or 500 ms trace interval is hippocampal dependent. However, training with the post-US cue was not hippocampal dependent. The majority of lesion rats in this condition reached criterion of conditioned responding. To determine whether hippocampal dependence is sufficient to rescue adult-generated neurons in the dentate gyrus, rats were injected with BrdU and trained in one of the three trace eyeblink arrangements one week later. Of these training procedures, only the 500 ms trace interval enhanced survival of new cells; acquisition of this task proceeded slowly relative to the 250 ms and post-US cue conditions. These data demonstrate that rate of acquisition and not hippocampal dependence determines the impact of learning on adult neurogenesis.

Neurobiology of Learning and Memory, 2010

Exposure to acute, inescapable stress produces a facilitation of subsequent classical eyeblink co... more Exposure to acute, inescapable stress produces a facilitation of subsequent classical eyeblink conditioning in male rats. The same stress exposure produces a profound deficit in classical eyeblink conditioning in females. Activation of N-methyl-D-aspartate receptors (NMDAr) is necessary for the effect of stress on learning in males while the contribution of NMDAr activation to the deficit in learning after stress is unknown. Here, we tested the influence of D-cycloserine (DCS), a positive modulator of the NMDAr, in stressed or unstressed male and female rats. Groups of males and females were exposed to an acute stressful event. One day later, they began training with four sessions of trace eyeblink conditioning. Each day before training, they were injected with DCS (15 mg/kg) or saline. Females treated with DCS during training responded similarly to those that were untreated. However, those that were stressed and the next day treated with the drug during training did not express the typical learning deficit, i.e. they learned to time the CR very well. Because the drug was administered well after the stressor, these data indicate that DCS reversed the negative effects of stress on learning in females. In males, the effect of DCS was subtle, resulting in higher asymptotic responding, and enhanced retention in a drug-free retention test. Thus, as shown previously, training in the presence of an NMDA receptor agonist enhances associative learning and memory retention. In addition, it can reverse learning deficits that have already been induced.

Journal of Neurochemistry, 2012

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is studied i... more Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is studied in the Fmr1 knockout (KO) mouse, which models both the anatomical and behavioral changes observed in FXS patients. In vitro studies have shown many alterations in synaptic plasticity and increased density of immature dendritic spines in the hippocampus, a region involved in learning and memory. In this study, magnetic resonance imaging (MRI) and 1 H magnetic resonance spectroscopy (MRS) were used to determine in vivo longitudinal changes in volume and metabolites in the hippocampus during the critical period of early myelination and synaptogenesis at post-natal days (PND) 18, 21, and 30 in Fmr1 KO mice compared with wild-type (WT) controls. MRI demonstrated an increase in volume of the hippocampus in the Fmr1 KO mouse compared with controls. MRS revealed significant developmental changes in the ratios of hippocampal metabolites N-acetylaspartate (NAA), myo-inositol (Ins), and taurine to total creatine (tCr) in Fmr1 KO mice compared with WT controls. Ins was decreased at PND 30, and taurine was increased at all ages studied in Fmr1 KO mice compared with controls. An imbalance of brain metabolites in the hippocampus of Fmr1 KO mice during the critical developmental period of synaptogenesis and early myelination could have long-lasting effects that adversely affect brain development and contribute to ongoing alterations in brain function.

Journal of Experimental Psychology: Animal Behavior Processes, 2008

Four experiments with rats studied the effects of switching the context after Pavlovian condition... more Four experiments with rats studied the effects of switching the context after Pavlovian conditioning. In three conditioned suppression experiments, a large number of conditioning trials created "inhibition with reinforcement" (IWR), in which fear of the conditional stimulus (CS) reached a maximum and then declined despite continued CS -unconditional stimulus pairings. When IWR occurred, a context switch augmented fear of the CS; IWR and augmentation were highly correlated. Neither IWR nor augmentation resulted from inhibition of delay (IOD): In conditioned suppression, IWR and augmentation occurred without IOD (Experiment 3), and in appetitive conditioning (Experiment 4), IOD occurred without IWR or augmentation. IWR may occur in conditioned suppression because the animal adapts to fear of the CS in a context-specific manner. We discuss several implications.

Hormones and Behavior, 2013

The first two weeks of life are a critical period for hippocampal development. At this time gonad... more The first two weeks of life are a critical period for hippocampal development. At this time gonadal steroid exposure organizes sex differences in hippocampal sensitivity to activational effects of steroids, hippocampal cell morphology and hippocampus dependent behaviors. Our laboratory has characterized a robust sex difference in neonatal neurogenesis in the hippocampus that is mediated by estradiol. Here, we extend our knowledge of this sex difference by comparing the male and female hippocampus to the androgen insensitive testicular feminized mutant (Tfm) rat. In the neonatal Tfm rat hippocampus, fewer newly generated cells survive compared to males or females. This deficit in cell genesis is partially recovered with the potent androgen DHT, but is more completely recovered following estradiol administration. Tfm rats do not differ from males or females in the level of endogenous estradiol in the neonatal hippocampus, suggesting other mechanisms mediate a differential sensitivity to estradiol in male, female and Tfm hippocampus. We also demonstrate disrupted performance on a hippocampal-dependent contextual fear discrimination task. Tfm rats generalize fear across contexts, and do not exhibit significant loss of fear during extinction exposure. These results extend prior reports of exaggerated response to stress in Tfm rats, and following gonadectomy in normal male rats.

European Journal of Neuroscience, 2008

Though the role of the hippocampus in processes of learning and memory is well established, the r... more Though the role of the hippocampus in processes of learning and memory is well established, the role of new neurons generated there is less understood. Training on some associative learning tasks increases the likelihood that new cells in the subgranular zone of the dentate gyrus will survive. In the rat, an effective training procedure is trace eyeblink conditioning, in which a conditioned stimulus (CS) is paired with an aversive stimulation to the eyelid (unconditioned stimulus; US), but the stimuli are separated by a temporal gap. Here, we manipulated the asymptote or rate of acquisition during trace conditioning, and examined survival of cells generated 1 week before training. Acquisition was disrupted by decreasing associative strength by insertion of unpredicted USs or slowed with latent inhibition. The number of cells was increased in animals that were trained with trace conditioning, irrespective of the decrease in associative strength or slowed acquisition. Disrupting acquisition with unsignaled USs still increased cell numbers, suggesting that the learning effect on cell survival is not dependent on reliable expression of the conditioned response. Further, animals in the latent inhibition conditions that learned but required more trials also retained more of the new cells than animals requiring fewer trials. The number of cells that survived after the effective training procedures was similar to the number of cells that were available for rescue at the beginning of training. Thus, learning can rescue the majority of cells expressed at the beginning of training, and does so most effectively when acquisition requires many trials.

British Journal of Pharmacology, 2014

Dynamin-related protein 1 (Drp1) mediates mitochondrial fission and is thought to promote Bax/Bak... more Dynamin-related protein 1 (Drp1) mediates mitochondrial fission and is thought to promote Bax/Bak-induced cytochrome c release during apoptosis. Conformationally active Bax, Bak and Bax/Bak-activating BH3-only proteins, such as Bim, are restrained by anti-apoptotic Bcl-2 proteins in cells that are 'primed for death'. Inhibition of Bcl-2/Bcl-xL/Bcl-w by the antagonist ABT-737 causes rapid apoptosis of primed cells. Hence, we determined whether Drp1 is required for cytochrome c release, respiratory alterations and apoptosis of cells that are already primed for death. We tested the Drp1 inhibitor mdivi-1 for inhibition of cytochrome c release in MCF10A cells primed by Bcl-2 overexpression. We measured ATP synthesis-dependent, -independent and cytochrome c-limited maximal oxygen consumption rates (OCRs) and cell death of immortalized wild-type (WT) and Drp1 knockout (KO) mouse embryonic fibroblasts (MEFs) treated with ABT-737. Mdivi-1 failed to attenuate ABT-737-induced cytochrome c release. ABT-737 decreased maximal OCR measured in the presence of uncoupler in both WT and Drp1 KO MEF, consistent with respiratory impairment due to release of cytochrome c. However, Drp1 KO MEF were slightly less sensitive to this ABT-737-induced respiratory inhibition compared with WT, and were resistant to an initial ABT-737-induced increase in ATP synthesis-independent O2 consumption. Nevertheless, caspase-dependent cell death was not reduced. Pro-apoptotic Bax was unaltered, whereas Bak was up-regulated in Drp1 KO MEF. The findings indicate that once fibroblast cells are primed for death, Drp1 is not required for apoptosis. However, Drp1 may contribute to ABT-737-induced respiratory changes and the kinetics of cytochrome c release.

Behavioural Brain Research, 2004

While a number of studies have examined the acquisition and expression of conditioned fear in inb... more While a number of studies have examined the acquisition and expression of conditioned fear in inbred mice, very few have examined extinction of conditioned fear in inbred mice and few attempts have been made to compare extinction learning between inbred strains. Because inbred strains differ in a number of physiological and biochemical variables, differences in extinction learning may provide insight into the genetic influence of extinction learning. The purpose of this study was to examine extinction and renewal of conditioned fear in two common inbred strains of mice. C57BL/6J and DBA/2J mice were conditioned with pairings of either a tone or light and foot shock in a single session. On the following 4 days, mice were given extinction training, consisting of tone or light alone trials (Experiment 1A). C57 mice exhibited robust spontaneous recovery between sessions, but did extinguish both within and between sessions. DBA mice extinguished more quickly relative to C57 mice, and this extinction was stable between sessions (i.e., DBA mice did not exhibit spontaneous recovery). The rapid loss of fear in DBA relative to C57 mice was extinction-dependent and not merely due to poor long-term memory (Experiment 1B). Renewal testing (Experiment 2) replicated the strain difference in extinction and also showed that DBA mice have a deficit in the context specificity of extinction. C57 mice, but not DBA mice showed renewal of extinguished fear when tested in a context different from the one in which extinction training took place. These data suggest that the nature of extinction learning is influenced by characteristics of the inbred mouse strain.

Behavioural Brain Research, 2003

Though much is known about the neural circuits involved in the elicitation of fear, little is kno... more Though much is known about the neural circuits involved in the elicitation of fear, little is known about the neural circuits responsible for the reduction of fear. The present experiments investigated the contribution of the superior colliculus (SC) and the dorsal periacquaductal gray (dPAG) in the reduction of conditioned fear produced by an auditory feature trained in a feature-negative discrimination procedure. In this procedure, light plus foot shock training trials are interspersed with trials in which the light is preceded by a noise and this noise and light compound is not followed by foot shock. At the end of this feature-negative discrimination training, rats were given excitotoxic lesions of the SC or dPAG. Feature-negative discrimination of fear was assessed with the fear-potentiated startle effect in which conditioned fear is operationally defined as potentiated startle amplitude in the presence versus the absence of the light. Feature-negative discrimination of fear is evidenced by a reduction in fear-potentiated startle to the light when the noise feature accompanies the light. Lesions of the SC, but not the dPAG, interfered with feature-negative discrimination of fear-potentiated startle suggesting that the SC plays a role in feature-negative discrimination of fear. Both SC and dPAG lesions facilitated startle amplitude in the absence of the light suggesting that these structures may exert a tonic inhibition on the acoustic startle reflex. The SC receives polymodal sensory information and is known to project forebrain areas involved in the production of conditioned fear. Thus, the SC may be an important component of the feature-negative discrimination circuit.

Behavioral Neuroscience, 2006

Four experiments investigated the effects of lesions of the bed nucleus of the stria terminalis (... more Four experiments investigated the effects of lesions of the bed nucleus of the stria terminalis (BNST) on conditioned fear and anxiety. Though BNST lesions did not disrupt fear conditioning with a shortduration conditional stimulus (CS; Experiments 1 and 3), the lesion attenuated conditioning with a longer duration CS (Experiments 1 and 2). Experiment 3 found that lesions attenuated reinstatement of extinguished fear, which relies on contextual conditioning. Experiment 4 confirmed that the lesion reduced unconditioned anxiety in an elevated zero maze. The authors suggest that long-duration CSs, whether explicit cues or contexts, evoke anxiety conditioned responses, which are dissociable from fear responses to shorter CSs. Results are consistent with behavioral and anatomical distinctions between fear and anxiety and with a behavior-systems view of defensive conditioning.

Behavioral Neuroscience, 2008

The present experiments assessed the necessity of central CRF in reinstatement of extinguished fe... more The present experiments assessed the necessity of central CRF in reinstatement of extinguished fear. Using the fear-potentiated startle procedure, rats were given light-shock pairings (fear conditioning) followed by light-alone extinction training. Rats were then given unsignaled shocks to reinstate fear to the light conditioned stimulus (CS). Intracerebroventricular administration of the CRF antagonist a-Helical CRF9-41 prior to reinstatement training dose-dependently prevented reinstatement. Further, a-Helical CRF9-41 administration prior to reinstatement training or the test for reinstatement of fear to the extinguished CS prevented reinstatement at both treatment times, suggesting that CRF activity is critical for this type of return of fear to an extinguished CS. The abolition of reinstatement by drug administration was not due to state-dependent learning, as rats treated with the drug prior to both reinstatement training or testing also failed a-Helical CRF9-41 in the bed nucleus of the stria terminalis suggested that this area is a site at which central CRF is involved in this form of relapse.

Biology of Sex Differences, 2010

Background: Oestradiol is a steroid hormone that exerts extensive influence on brain development ... more Background: Oestradiol is a steroid hormone that exerts extensive influence on brain development and is a powerful modulator of hippocampal structure and function. The hippocampus is a critical brain region regulating complex cognitive and emotional responses and is implicated in the aetiology of several mental health disorders, many of which exhibit some degree of sex difference. Many sex differences in the adult rat brain are determined by oestradiol action during a sensitive period of development. We had previously reported a sex difference in rates of cell genesis in the developing hippocampus of the laboratory rat. Males generate more new cells on average than females. The current study explored the effects of both exogenous and endogenous oestradiol on this sex difference.