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Papers by Ann Goodchild

Disinhibition of the midbrain colliculi unmasks coordinated autonomic, respiratory, and somatomotor responses to auditory and visual stimuli

American journal of physiology. Regulatory, integrative and comparative physiology, Jan 15, 2014

The midbrain superior and inferior colliculi have critical roles in generating coordinated orient... more The midbrain superior and inferior colliculi have critical roles in generating coordinated orienting or defensive behavioral responses to environmental stimuli, and it has been proposed that neurons within the colliculi can also generate appropriate cardiovascular and respiratory responses to support such behavioral responses. We have previously shown that activation of neurons within a circumscribed region in the deep layers of the superior colliculus and in the central and external nuclei of the inferior colliculus can evoke a response characterized by intense and highly synchronized bursts of renal sympathetic nerve activity and phrenic nerve activity. In this study, we tested the hypothesis that, under conditions in which collicular neurons are disinhibited, coordinated cardiovascular, somatomotor, and respiratory responses can be evoked by natural environmental stimuli. In response to natural auditory, visual, or somatosensory stimuli, powerful synchronized increases in sympath...

Serotonin (5HT) is crucial to normal reflex vagal modulation of heart rate (HR). Reduced barorefl... more Serotonin (5HT) is crucial to normal reflex vagal modulation of heart rate (HR). Reduced baroreflex sensitivity (sBRS) and HR variability (HRV) reflect impaired neural, particularly vagal, control of HR and are independently associated with depression. In conscious, telemetered Flinders-Sensitive Line rats (FSL), a well-validated animal model of depression, we tested the hypothesis that cardiovascular regulatory abnormalities are present and associated with deficient serotonergic control of reflex cardio-vagal function. In FSL, and control Flinders-Resistant rat (FRL) and Sprague Dawley rat (SD) strains, diurnal measurements of HR, arterial pressure (AP), activity, sBRS and HRV were made. All strains had normal and similar diurnal variations in HR, AP and activity. HR was elevated in FRL contributing to the reduced HRV and sBRS seen in this strain. FSL had reduced sBRS and high frequency power HRV during the night indicating reduced reflex cardio-vagal activity. The ratio of low to high frequency bands of HRV was increased in FSL suggesting a relative predominance of cardiac sympathetic and/or reflex activity compared to FRL and SD. These data show that conscious FSL have cardiovascular regulatory abnormalities similar to depressed humans. Acute changes in HR, AP, temperature and sBRS to 8-OHDPAT, 5HT-1A/1B/7 receptor agonist, were also determined. In FSL, despite inducing an exaggerated hypothermic effect, 8-OHDPAT did not decrease HR and AP or improve sBRS suggesting impaired serotonergic neural control of cardio-vagal activity.

Spontaneously hypertensive rats (SHR) are characterized by extreme elevations of blood pressure. ... more Spontaneously hypertensive rats (SHR) are characterized by extreme elevations of blood pressure. The genetic factors underlying this are yet to be identified. Here we demonstrate, in vivo, that in SHR and normotensive Wistar-Kyoto rats (WKY), injection of the mitogen-activated protein kinase inhibitor PD 098,059 bilaterally into the rostral ventrolateral medulla (RVLM) dramatically lowers arterial pressure. PD 098,059 does not alter

In this study we aimed to determine whether the levels of gene expression for phenylethanolamine-... more In this study we aimed to determine whether the levels of gene expression for phenylethanolamine-N- methyltransferase (PNMT), noradrenaline transporter (NAT), 1A-receptor (1A-R), and 2A-receptor (2A-R) vary with resting systolic blood pressure in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) or Sprague-Dawley (SD) rats. Sites examined included central and peripheral regions associated with the control of arterial pressure. Twenty

Physiological reports, 2015

Genetic tools that permit functional or connectomic analysis of neuronal circuits are rapidly tra... more Genetic tools that permit functional or connectomic analysis of neuronal circuits are rapidly transforming neuroscience. The key to deployment of such tools is selective transfection of target neurons, but to date this has largely been achieved using transgenic animals or viral vectors that transduce subpopulations of cells chosen according to anatomical rather than functional criteria. Here, we combine single-cell transfection with conventional electrophysiological recording techniques, resulting in three novel protocols that can be used for reliable delivery of conventional dyes or genetic material in vitro and in vivo. We report that techniques based on single cell electroporation yield reproducible transfection in vitro, and offer a simple, rapid and reliable alternative to established dye-labeling techniques in vivo, but are incompatible with targeted transfection in deep brain structures. In contrast, we show that intracellular electrophoresis of plasmid DNA transfects brainst...

European Journal of Neuroscience, 2014

Identifying neurons essential for the generation of breathing and related behaviors such as vocal... more Identifying neurons essential for the generation of breathing and related behaviors such as vocalisation is an important question for human health. The targeted loss of preB€ otzinger Complex (preB€ otC) glutamatergic neurons, including those that express high levels of somatostatin protein (SST neurons), eliminates normal breathing in adult rats. Whether preB€ otC SST neurons represent a functionally specialised population is unknown. We tested the effects on respiratory and vocal behaviors of eliminating SST neuron glutamate release by Cre-Lox-mediated genetic ablation of the vesicular glutamate transporter 2 (VGlut2). We found the targeted loss of VGlut2 in SST neurons had no effect on viability in vivo, or on respiratory period or responses to neurokinin 1 or l-opioid receptor agonists in vitro. We then compared medullary SST peptide expression in mice with that of two species that share extreme respiratory environments but produce either high or low frequency vocalisations. In the Mexican free-tailed bat, SST peptide-expressing neurons extended beyond the preB€ otC to the caudal pole of the VII motor nucleus. In the naked molerat, however, SST-positive neurons were absent from the ventrolateral medulla. We then analysed isolation vocalisations from SST-Cre;VGlut2 F/F mice and found a significant prolongation of the pauses between syllables during vocalisation but no change in vocalisation number. These data suggest that glutamate release from preB€ otC SST neurons is not essential for breathing but play a species-and behavior-dependent role in modulating respiratory networks. They further suggest that the neural network generating respiration is capable of extensive plasticity given sufficient time.

Brain Sciences, 2012

The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) often results in chronic treatme... more The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) often results in chronic treatment with psychostimulants such as methylphenidate (MPH, Ritalin ® ). With increases in misdiagnosis of ADHD, children may be inappropriately exposed to chronic psychostimulant treatment during development. The aim of this study was to assess the effect of chronic Ritalin treatment on cognitive and neural development in misdiagnosed "normal" (Wistar Kyoto, WKY) rats and in Spontaneously Hypertensive Rats (SHR), a model of ADHD. Adolescent male animals were treated for four weeks with oral Ritalin ® (2 × 2 mg/kg/day) or distilled water (dH 2 O). The effect of chronic treatment on delayed reinforcement tasks (DRT) and tyrosine hydroxylase immunoreactivity (TH-ir) in the prefrontal cortex was assessed. Two weeks following chronic treatment, WKY rats previously exposed to MPH chose the delayed reinforcer significantly less than the dH 2 O treated controls in both the DRT and extinction task. MPH treatment did not significantly alter cognitive performance in the SHR. TH-ir in the infralimbic cortex was significantly altered by age and behavioural experience in WKY and SHR, however this effect was not evident in WKY rats treated with MPH. These results suggest that chronic treatment with MPH throughout adolescence in "normal" WKY rats increased impulsive choice and altered catecholamine development when compared to vehicle controls. OPEN ACCESS Brain Sci. 2012, 2 376

The distribution of calcium-binding proteins in the lateral geniculate nucleus and visual cortex of a New World monkey, the marmoset, Callithrix jacchus

Visual Neuroscience, 1998

Antibodies directed against the calcium-binding proteins, parvalbumin and calbindin, can be used ... more Antibodies directed against the calcium-binding proteins, parvalbumin and calbindin, can be used to label distinct neuronal subgroups in the primate visual pathway. We analyzed parvalbumin immunoreactivity (P-IR) and calbindin immunoreactivity (C-IR) in the lateral geniculate nucleus (LGN) and visual cortex of the marmoset, Callithrix jacchus. We compared marmosets which were identified as having dichromatic or trichromatic color vision. Within the LGN, the density of P-IR neurones is highest in the parvocellular and magnocellular laminae, but C-IR neurones are found mainly in the koniocellular division of the LGN, that is, the interlaminar zones and S laminae. Not all interlaminar zone cells are C-IR. In the visual cortex, P-IR neurones are present in all laminae except lamina 1, in areas V1 and V2. Neurones which are strongly C-IR are mainly located in laminae 2 and 3 in V1 and V2. Lightly C-IR neurones are concentrated in lamina 4, and are more numerous in V1 than in V2. Quantitative analysis showed no differences in the density or distribution of IR neurones in either LGN or visual cortex when dichromat and trichromat animals were compared. We conclude that this functional difference is not associated with differences in the neurochemistry of calcium-binding proteins in the primary visual pathways.

Respiratory, metabolic and cardiac functions are altered by disinhibition of subregions of the medial prefrontal cortex

The Journal of Physiology, 2013

The prefrontal cortex (PFC) is referred to as the visceral motor cortex; however, little is known... more The prefrontal cortex (PFC) is referred to as the visceral motor cortex; however, little is known about whether this region influences respiratory or metabolic outflows. The aim of this study was to describe simultaneous changes in respiratory, metabolic and cardiovascular functions evoked by disinhibition of the medial PFC (mPFC) and adjacent lateral septal nucleus (LSN). In urethane-anaesthetized rats, bicuculline methiodide was microinjected (2 mm; GABA-A receptor antagonist) into 90 sites in the mPFC at 0.72-4.00 mm from bregma. Phrenic nerve amplitude and frequency, arterial pressure, heart rate, splanchnic and lumbar sympathetic nerve activities (SNA), expired CO2, and core and brown adipose tissue temperatures were measured. Novel findings included disturbances to respiratory rhythm evoked from all subregions of the mPFC. Injections into the cingulate cortex evoked reductions in central respiratory function exclusively, whereas in ventral sites, particularly the infralimbic region, increases in respiratory drive and frequency, and metabolic and cardiac outflows were evoked. Disinhibition of sites in surrounding regions revealed that the LSN could evoke cardiovascular changes accompanied by distinct oscillations in SNA, as well as increases in respiratory amplitude. We show that activation of neurons within the mPFC and LSN influence respiratory, metabolic and cardiac outflows in a site-dependent manner. This study has implications with respect to the altered PFC neuronal activity seen in stress-related and mental health disorders, and suggests how basic physiological systems may be affected.

Substance P inputs to laryngeal motoneurons in the rat

Respiratory Physiology & Neurobiology, 2003

Substance P terminals have previously been demonstrated around retrogradely labelled posterior cr... more Substance P terminals have previously been demonstrated around retrogradely labelled posterior cricoarytenoid (PCA) motoneurons, but little is known regarding substance P inputs to other functionally identified laryngeal motoneurons. In the present study, we determined the number and distribution of close appositions between substance P immunoreactive boutons and three types of laryngeal motoneuron by using a combination of intracellular recording, dye-filling and immunocytochemistry in the rat. Cricothyroid (CT) motoneurons received 15+/-5 substance P appositions/neuron (mean+/-S.D., n = 6), PCA motoneurons received 13+/-5 (n = 6), and laryngeal constrictor (LCS) motoneurons received 11+/-4 (n = 5). In contrast to our previous finding of a preferential serotonin innervation of CT motoneurons, we found no significant difference between the substance P inputs to CT, PCA and LCS motoneurons. Our results indicate a modest role for substance P in control of laryngeal motoneuronal function.

Neuroscience, 2012

About 860 G-protein-coupled receptors (GPCRs) mediate their actions via heterotrimeric G-proteins... more About 860 G-protein-coupled receptors (GPCRs) mediate their actions via heterotrimeric G-proteins. Their activation releases Ga from Gbk subunits. The type of Ga subunit dictates the major signalling proteins involved: adenylyl cyclase, PLC and rhoGEF. The rostral ventrolateral medulla (RVLM), containing the rostral C1 (rC1) cell group, sets and maintains the tonic and reflex control of blood pressure and a plethora of inputs converge onto these neurons. We determined the relative abundance of 10 Ga subunit mRNAs, representing the four major families, within the RVLM, using quantitative RT-PCR. In situ hybridisation (ISH) combined with immunohistochemistry (IHC) was used to quantify and compare this expression in rC1 with that in the A1 and A5 cell groups. The relative abundance of Ga subunit mRNAs and a comparison of gene expression levels were quantitatively determined in normotensive and hypertensive rat strains. All 10 Ga mRNAs were detected in the RVLM of Sprague-Dawley (SD) rats with relative abundance such that Gas > Gai2 > Gao > Gaq > GaL > Ga11 > Gai3 > Gai1 > Ga12 > Ga13. The high abundance of Ga mRNAs signalling via adenylyl cyclase indicates the importance of associated GPCRs. Within the rC1 and A1 groups similar differential Ga mRNA expression profiles were seen with Gas being found in all rC1 cells, Ga11 absent and Gai3 rarely expressed. Thus functionally distinct subgroups exist within the rC1 and A1 cell groups as differing distributions of Ga subunits must reflect the array of GPCRs that influence their activity. In contrast, all A5 cells expressed all Ga mRNAs suggesting a functionally homogeneous group. When the 10 Ga mRNAs of the RVLM in spontaneously hypertensive rats (SHR) were compared quantitatively to Wistar-Kyoto (WKY), only Gas and Ga12 were significantly elevated. However when the expression in normotensive SD and WKY was compared with SHR no significant differ-ences were evident. These findings demonstrate a range of GPCR signalling capabilities in brainstem neurons important for homeostasis and suggest a prominent role for signalling via adenylyl cyclase. Ó

Neuroscience, 2010

Chemical coding of sympathetic preganglionic neurons (SPN) suggests that the chemical content of ... more Chemical coding of sympathetic preganglionic neurons (SPN) suggests that the chemical content of subpopulations of SPN can define their function. Since neuropeptides, once synthesized are transported to the axon terminal, most demonstrated chemical coding has been identified using immunoreactive terminals at the target organ. Here, we use a different approach to identify and quantify the subpopulations of SPN that contain the mRNA for pituitary adenylate cyclase activating polypeptide (PACAP) or enkephalin. Using double-labeled immunohistochemistry combined with in situ hybridization (ISH) we firstly identified the distribution of these mRNAs in the spinal cord and determined quantitatively, in Sprague-Dawley rats, that many SPN at the T4-T10 spinal level contain preproPACAP (PPP؉, 80؎3%, n‫,)3؍‬ whereas a very small percentage contain preproenkephalin (PPE؉, 4؎2%, n‫.)4؍‬ A similar neurochemical distribution was found at C8-T3 spinal level. These data suggest that PACAP potentially regulates a large number of functions dictated by SPN whereas enkephalins are involved in few functions. We extended the study to explore those SPN that control adrenal chromaffin cells. We found 97؎5% of adrenally projecting SPN (AP-SPN) to be PPP؉ (n‫)4؍‬ with only 47؎3% that were PPE؉ (n‫.)5؍‬ These data indicate that adrenally projecting PACAPergic SPN regulate both adrenal adrenaline (Ad) and noradrenaline (NAd) release whereas the enkephalinergic SPN subpopulation must control a (sub) population of chromaffin cells -most likely those that release Ad. The sensory innervation of the adrenal gland was also determined. Of the few adrenally projecting dorsal root ganglia (AP-DRG) observed, 74؎12% were PPP؉ (n‫,)3؍‬ whereas 1؎1% were PPE؉ (n‫.)3؍‬ Therefore, if sensory neurons release peptides to the adrenal medulla, PACAP is most likely involved. Together, these data provide a neurochemical basis for differential control of sympathetic outflow particularly that to the adrenal medulla.

Delta pioid receptor immunoreactive boutons appose bulbospinal CI neurons in the rat

NeuroReport, 2000

ABSTRACT

NK1 receptor and the ventral medulla of the rat: bulbospinal and catecholaminergic neurons

Neuroreport, 2001

Bulbospinal C1 neurons are sympathoexcitatory and excited by substance P. However the substance P... more Bulbospinal C1 neurons are sympathoexcitatory and excited by substance P. However the substance P receptor (NK1 receptor), has been reported to be absent from the somata of C1 neurons. In this study, using double and triple labelling immunofluorescence and retrograde tracing, we provide evidence that the NK1 receptor is present on 5.3% of C1 neurons, and that 4.7% of C1 neurons receive close oppositions from NK1 receptor immunoreactive terminals, indicating a pre-synaptic and post-synaptic site for the action of substance P. These results provide support for the sympathoexcitatory actions of substance P on C1 neurons. We also demonstrate the NK1 receptor on bulbospinal neurons of the ventral respiratory group, in a region overlapping the pre-Bötzinger Complex.

Behavioral and Neural Substrates of Habit Formation in Rats Intravenously Self-Administering Nicotine

Neuropsychopharmacology, 2014

Tobacco addiction involves a transition from occasional, voluntary smoking towards habitual behav... more Tobacco addiction involves a transition from occasional, voluntary smoking towards habitual behavior that becomes increasingly resistant to quitting. The development of smoking habits may reflect a loss of behavioral control that can be modeled in rats. This study investigated the behavioral and neural substrates of habit formation in rats exposed to either brief (10 days) or extended (47 days) intravenous (IV) nicotine self-administration training. Following training, the first cohort of rats were exposed to a nicotine devaluation treatment, which involved repeated pairings of IV nicotine with lithium injection. They were then tested for sensitivity of responding to nicotine devaluation under extinction and reinstatement conditions. The second cohort of rats received equivalent self-administration training followed by processing of brain tissue for c-Fos immunohistochemistry. After brief training, devaluation suppressed nicotine-seeking during tests of extinction and reinstatement, confirming that responding is initially sensitive to current nicotine value, and therefore, goal directed. In contrast, after extended training, devaluation had no effect on extinction or reinstatement of responding, indicating that responding had become habitual. Complementary neuroanalysis revealed that extended nicotine self-administration was associated with increased c-Fos expression in brain regions implicated in habitual control of reward seeking, including activation of the dorsolateral striatum and substantia nigra pars compacta. These findings provide evidence of direct devaluation of an IV drug reward, that nicotine self-administration is initially goal-directed but becomes habitual with extended training, and that this behavioral transition involves activation of brain areas associated with the nigrostriatal system.

Journal of Hypertension, 2009

Objective We demonstrated previously that central muscarinic cholinergic receptor (mAChR) activat... more Objective We demonstrated previously that central muscarinic cholinergic receptor (mAChR) activation increased splanchnic sympathetic nerve activity and sympathetic baroreflex function via activation of mAChR in the rostral ventrolateral medulla (RVLM), and we found that some RVLM bulbospinal neurons contain muscarinic M2R mRNA. Here, we examined the gene expression, cellular distribution and functional role of muscarinic receptors in the RVLM in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto (WKY) rats.

The Journal of Comparative Neurology, 2001

Adrenergic (C1) neurons located in the rostral ventrolateral medulla are considered a key compone... more Adrenergic (C1) neurons located in the rostral ventrolateral medulla are considered a key component in the control of arterial blood pressure. Classically, C1 cells have been identified by their immunoreactivity for the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH) and/or phenylethanolamine N-methyltransferase (PNMT). However, no studies have simultaneously demonstrated the expression of aromatic L-amino acid decarboxylase (AADC) and dopamine ␤-hydroxylase (DBH) in these neurons. We examined the expression and colocalization of all four enzymes in the rat ventrolateral medulla using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Retrograde tracer injected into thoracic spinal segments T2-T4 was used to identify bulbospinal neurons. Using fluorescence and confocal microscopy, most cells of the C1 group were shown to be double or triple labeled with TH, DBH, and PNMT, whereas only 65-78% were immunoreactive for AADC. Cells that lacked detectable immunoreactivity for AADC were located in the rostral C1 region, and approximately 50% were spinally projecting. Some cells in this area lacked DBH immunoreactivity (6.5-8.3%) but were positive for TH and/or PNMT. Small numbers of cells were immunoreactive for only one of the four enzymes. Numerous fibres that were immunoreactive for DBH but not for TH or PNMT were noted in the rostral C1 region. Single-cell RT-PCR analysis conducted on spinally projecting C1 neurons indicated that only 76.5% of cells that contained mRNA for TH, DBH, and PNMT contained detectable message for AADC. These experiments suggest that a proportion of C1 cells may not express all of the enzymes necessary for adrenaline synthesis.

Comparison of photoreceptor spatial density and ganglion cell morphology in the retina of human, macaque monkey, cat, and the marmosetCallithrix jacchus

The Journal of Comparative Neurology, 1996

We studied the relationship between the morphology of ganglion cells and the spatial density of p... more We studied the relationship between the morphology of ganglion cells and the spatial density of photoreceptors in the retina of two Old World primates, human and macaque monkey; the diurnal New World marmoset Callithrix jacchus; and the cat. Ganglion cells in macaque and marmoset were labelled by intracellular injection with Neurobiotin or by DiI diffusion labelling in fixed tissue. Cone photoreceptor densities were measured from the same retinas. Supplemental data for macaque and data for human and cat were taken from published studies. For the primates studied, the central retina is characterised by a constant numerical convergence of cones to ganglion cells. Midget ganglion cells derive their input, via a midget bipolar cell, from a single cone. Parasol cells derive their input from 40-140 cones. Outside the central retina, the convergence increases with eccentricity. The convergence to beta cells in the cat retina is very close to that for parasol cells in primate retina. The convergence of rod photoreceptors to ganglion cells is similar in human, macaque, and marmoset, with parasol cells receiving input from 10-15 times more rods than midget cells. The low convergence of cones to midget cells in human and macaque retinas is associated with distinctive dendritic "clusters" in midget cells' dendritic fields. Convergence in marmoset is higher, and the clusters are absent. We conclude that the complementary changes in photoreceptor density and ganglion cell morphology should be considered when forming linking hypotheses between dendritic field, receptive field, and psychophysical properties of primate vision.

Serotonin inputs to inspiratory laryngeal motoneurons in the rat

The Journal of Comparative Neurology, 2002

Serotonergic neurons are distributed widely throughout the central nervous system and exert a ton... more Serotonergic neurons are distributed widely throughout the central nervous system and exert a tonic influence on a range of activities in relation to the sleep-wake cycle. Previous morphologic and functional studies have indicated a role for serotonin in control of laryngeal motoneurons. In the present study, we used a combination of intracellular recording, dye-filling, and immunocytochemistry in rats to demonstrate close appositions between serotonin immunoreactive boutons and posterior cricoarytenoid (PCA) and cricothyroid (CT) motoneurons, both of which are located in the nucleus ambiguus and exhibit phasic inspiratory activity. PCA motoneurons received 29 +/- 5 close appositions/neuron (mean +/- SD, n = 6), with the close appositions distributed more frequently on the distal dendrites, less frequently on the proximal dendrites, and sparsely on the axons and somata. CT motoneurons received 56 +/- 15 (n = 6), with close appositions found on both the somata and dendrites, especially proximal dendrites. Close appositions on the axons were only seen on one CT motoneuron. These results demonstrate a significant serotonin input to inspiratory laryngeal motoneurons, which is more prominent on CT compared with PCA motoneurons, and may reflect the different functional role of the muscles that they innervate during the sleep-wake cycle.

The Journal of Comparative Neurology, 2000