Amygdala central nucleus modulation of cerebellar learning in female rats.

Abstract Prolonged exposure to environmental stress activates the hypothalamic-pituitary-adrenal (HPA) axis and generally disrupts the hypothalamic-pituitary-gonadal axis. Because CRF expression in the central nucleus of the amygdala (CeA) is a key modulator in adaptation to chronic stress, and central administration of CRF inhibits the hypothalamic GnRH pulse generator, we tested the hypothesis that overexpression of CRF in the CeA of female rats alters anxiety behavior, dysregulates the HPA axis response to stress, changes pubertal timing, and disrupts reproduction. We used a lentiviral vector to increase CRF expression site specifically in the CeA of preweaning (postnatal day 12) female rats. Overexpression of CRF in the CeA increased anxiety-like behavior in peripubertal rats shown by a reduction in time spent in the open arms of the elevated plus maze and a decrease in social interaction. Paradoxically, puberty onset was advanced but followed by irregular estrous cyclicity and an absence of spontaneous preovulatory LH surges associated with proestrous vaginal cytology in rats overexpressing CRF. Despite the absence of change in basal corticosterone secretion or induced by stress (lipopolysaccharide or restraint), overexpression of CRF in the CeA significantly decreased lipopolysaccharide, but not restraint, stress-induced suppression of pulsatile LH secretion in postpubertal ovariectomized rats, indicating a differential stress responsivity of the GnRH pulse generator to immunological stress and a potential adaptation of the HPA axis to chronic activation of amygdaloid CRF. These data suggest that the expression profile of this key limbic brain CRF system might contribute to the complex neural mechanisms underlying the increasing incidence of early onset of puberty on the one hand and infertility on the other attributed to chronic stress in modern human society.

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Amygdala central nucleus modulation of cerebellar learning with a visual conditioned stimulus

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2018.03.011 ◽

2018 ◽

Vol 150 ◽

pp. 84-92 ◽

Cited By ~ 3

Author(s):

Sean J. Farley ◽

Heba Albazboz ◽

Benjamin J. De Corte ◽

Jason J. Radley ◽

John H. Freeman

Keyword(s):

Conditioned Stimulus ◽

Central Nucleus ◽

Cerebellar Learning

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Gonadal steroid receptors colocalize with central nervous system neurons projecting to the rat prostate gland

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00667.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. R2196-R2205 ◽

Cited By ~ 6

Author(s):

Gloria G. Huddleston ◽

C. Kay Song ◽

Jacquelyn C. Paisley ◽

Timothy J. Bartness ◽

Andrew N. Clancy

Keyword(s):

Mating Behavior ◽

Pseudorabies Virus ◽

Steroid Receptors ◽

Prostate Gland ◽

Copulatory Behavior ◽

Zona Incerta ◽

Female Rats ◽

Central Nucleus ◽

Male Rat ◽

Bed Nucleus

Mating-induced Fos-immunoreactive (-ir) cells are colocalized with androgen receptors (AR), estrogen receptors (ER), or both in limbic and hypothalamic areas known to mediate male rat mating behavior. A steroid-responsive neural network might govern copulatory behavior in male laboratory rats that is analogous to the network described in female rats that governs the lordosis response. This hypothesized network in males may synchronize and coordinate sexual behavioral responses with physiological responses of the genitals and the internal organs of reproduction. Therefore, the pseudorabies virus (PRV; Bartha strain), a transneuronal, viral retrograde tract tracer, was microinjected into the prostate gland to label this network. After 7 days, brains from infected animals were processed for immunohistochemical labeling of AR, ER, and PRV. The majority of PRV-ir cells exhibited either AR or ER immunoreactivity in the medial preoptic area, median preoptic nucleus, bed nucleus of stria terminalis, hypothalamic paraventricular nucleus, and zona incerta, areas known to play roles in male rat mating behavior. Other structures such as the central tegmental field/subparafascicular nucleus of the thalamus, central nucleus of the amygdala, and medial amygdala, also important in the display of male copulatory behavior, were less reliably labeled. Collectively, a steroid receptor-containing neuronal circuit, largely contained in the diencephalon, was revealed that likely is involved in the autonomic control of the prostate gland and the consummatory aspects of male rat mating behavior.

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Behavioral and brain mechanisms mediating conditioned flight behavior in rats

10.1101/2021.01.29.428848 ◽

2021 ◽

Author(s):

Michael S. Totty ◽

Naomi Warren ◽

Isabella Huddleston ◽

Karthik R. Ramanathan ◽

Reed L. Ressler ◽

...

Keyword(s):

Compound Stimulus ◽

Female Rats ◽

Flight Behavior ◽

Central Nucleus ◽

Stria Terminalis ◽

Conditioning Context ◽

Bed Nucleus ◽

Contextual Fear ◽

Male And Female Rats ◽

Innate Fear

ABSTRACTEnvironmental contexts and associative learning can inform animals of potential threats, though it is currently unknown how contexts bias defensive transitions. Here we investigated context-dependent flight responses in the Pavlovian serial-compound stimulus (SCS) paradigm. We show here that SCS-evoked flight behavior in male and female rats is dependent on contextual fear. Flight was reduced in the conditioning context after context extinction and could be evoked in a different shock-associated context. Although flight was exclusive to white noise stimuli, it was nonetheless associative insofar as rats that received an equal number of unpaired USs did not show flight-like behavior. Finally, we found that inactivation of either the central nucleus of the amygdala (CeA) or bed nucleus of the stria terminalis (BNST) attenuated both contextual fear and flight responses. This work demonstrates that contextual fear summates with cued and innate fear to drive a high fear state and freeze-to-flight transitions.

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Behavioral and brain mechanisms mediating conditioned flight behavior in rats

Scientific Reports ◽

10.1038/s41598-021-87559-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Michael S. Totty ◽

Naomi Warren ◽

Isabella Huddleston ◽

Karthik R. Ramanathan ◽

Reed L. Ressler ◽

...

Keyword(s):

Compound Stimulus ◽

Brain Regions ◽

Female Rats ◽

Flight Behavior ◽

Central Nucleus ◽

Male And Female ◽

Bed Nucleus ◽

Contextual Fear ◽

Male And Female Rats ◽

Context Dependent

AbstractEnvironmental contexts can inform animals of potential threats, though it is currently unknown how context biases the selection of defensive behavior. Here we investigated context-dependent flight responses with a Pavlovian serial-compound stimulus (SCS) paradigm that evokes freeze-to-flight transitions. Similar to previous work in mice, we show that male and female rats display context-dependent flight-like behavior in the SCS paradigm. Flight behavior was dependent on contextual fear insofar as it was only evoked in a shock-associated context and was reduced in the conditioning context after context extinction. Flight behavior was only expressed to white noise regardless of temporal order within the compound. Nonetheless, rats that received unpaired SCS trials did not show flight-like behavior to the SCS, indicating it is associative. Finally, we show that pharmacological inactivation of two brain regions critical to the expression of contextual fear, the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST), attenuates both contextual fear and flight responses. All of these effects were similar in male and female rats. This work demonstrates that contextual fear can summate with cued and innate fear to drive a high fear state and transition from post-encounter to circa-strike defensive modes.

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Self-Administration of Entactogen Psychostimulants Dysregulates Gamma-Aminobutyric Acid (GABA) and Kappa Opioid Receptor Signaling in the Central Nucleus of the Amygdala of Female Wistar Rats

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2021.780500 ◽

2021 ◽

Vol 15 ◽

Author(s):

Sophia Khom ◽

Jacques D. Nguyen ◽

Sophia A. Vandewater ◽

Yanabel Grant ◽

Marisa Roberto ◽

...

Keyword(s):

Opioid Receptor ◽

Wistar Rats ◽

Kappa Opioid Receptor ◽

Female Rats ◽

Central Nucleus ◽

Self Administration ◽

Kappa Opioid ◽

Extended Access ◽

Female Wistar Rats ◽

Saline Vehicle

Male rats escalate intravenous self-administration of entactogen psychostimulants, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxymethamphetamine (MDMA) under extended access conditions, as with typical psychostimulants. Here, we investigated whether female rats escalate self-administration of methylone, 3,4-methylenedioxypentedrone (pentylone), and MDMA and then studied consequences of MDMA and pentylone self-administration on GABAA receptor and kappa opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA), a brain area critically dysregulated by extended access self-administration of alcohol or cocaine. Adult female Wistar rats were trained to self-administer methylone, pentylone, MDMA (0.5 mg/kg/infusion), or saline-vehicle using a fixed-ratio 1 response contingency in 6-h sessions (long-access: LgA) followed by progressive ratio (PR) dose-response testing. The effects of pentylone-LgA, MDMA-LgA and saline on basal GABAergic transmission (miniature post-synaptic inhibitory currents, mIPSCs) and the modulatory role of KOR at CeA GABAergic synapses were determined in acute brain slices using whole-cell patch-clamp. Methylone-LgA and pentylone-LgA rats similarly escalated their drug intake (both obtained more infusions compared to MDMA-LgA rats), however, pentylone-LgA rats reached higher breakpoints in PR tests. At the cellular level, baseline CeA GABA transmission was markedly elevated in pentylone-LgA and MDMA-LgA rats compared to saline-vehicle. Specifically, pentylone-LgA was associated with increased CeA mIPSC frequency (GABA release) and amplitude (post-synaptic GABAA receptor function), while mIPSC amplitudes (but not frequency) was larger in MDMA-LgA rats compared to saline rats. In addition, pentylone-LgA and MDMA-LgA profoundly disrupted CeA KOR signaling such as both KOR agonism (1 mM U50488) and KOR antagonism (200 nM nor-binaltorphimine) decreased mIPSC frequency suggesting recruitment of non-canonical KOR signaling pathways. This study confirms escalated self-administration of entactogen psychostimulants under LgA conditions in female rats which is accompanied by increased CeA GABAergic inhibition and altered KOR signaling. Collectively, our study suggests that CeA GABA and KOR mechanisms play a critical role in entactogen self-administration like those observed with escalation of alcohol or cocaine self-administration.

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Stress-induced visceral pain in female rats is associated with epigenetic remodeling in the central nucleus of the amygdala

Neurobiology of Stress ◽

10.1016/j.ynstr.2021.100386 ◽

2021 ◽

Vol 15 ◽

pp. 100386

Author(s):

Tijs Louwies ◽

Albert Orock ◽

Beverley Greenwood-Van Meerveld

Keyword(s):

Visceral Pain ◽

Female Rats ◽

Central Nucleus ◽

Epigenetic Remodeling

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Estradiol treatment increases CCK-induced c-Fos expression in the brains of ovariectomized rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00300.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. R1378-R1385 ◽

Cited By ~ 38

Author(s):

Lisa A. Eckel ◽

Thomas A. Houpt ◽

Nori Geary

Keyword(s):

Food Intake ◽

Area Postrema ◽

Body Weight Gain ◽

Meal Size ◽

Female Rats ◽

Central Nucleus ◽

Ovariectomized Rats ◽

Estradiol Treatment ◽

Central Processing ◽

Fos Expression

The ovarian hormone estradiol reduces meal size and food intake in female rats, at least in part by increasing the satiating potency of CCK. Here we used c-Fos immunohistochemistry to determine whether estradiol increases CCK-induced neuronal activation in several brain regions implicated in the control of feeding. Because the adiposity signals leptin and insulin appear to control feeding in part by increasing the satiating potency of CCK, we also examined whether increased adiposity after ovariectomy influences estradiol's effects on CCK-induced c-Fos expression. Ovariectomized rats were injected subcutaneously with 10 μg 17β-estradiol benzoate (estradiol) or vehicle once each on Monday and Tuesday for 1 wk ( experiment 1) or for 5 wk ( experiment 2). Two days after the final injection of estradiol or vehicle, rats were injected intraperitoneally with 4 μg/kg CCK in 1 ml/kg 0.9 M NaCl or with vehicle alone. Rats were perfused 60 min later, and brain tissue was collected and processed for c-Fos immunoreactivity. CCK induced c-Fos expression in the nucleus of the solitary tract (NTS), area postrema (AP), paraventricular nucleus of the hypothalamus (PVN), and central nucleus of the amygdala (CeA) in vehicle- and estradiol-treated ovariectomized rats. Estradiol treatment further increased this response in the caudal, subpostremal, and intermediate NTS, the PVN, and the CeA, but not in the rostral NTS or AP. This action of estradiol was very similar in rats tested before ( experiment 1) and after ( experiment 2) significant body weight gain, suggesting that adiposity does not modulate CCK-induced c-Fos expression or interact with estradiol's ability to modulate CCK-induced c-Fos expression. These findings suggest that estradiol inhibits meal size and food intake by increasing the central processing of the vagal CCK satiation signal.

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An Enriched Environment Reduces Chronic Stress-Induced Visceral Pain Through Modulating Microglial Activity in the Central Nucleus of the Amygdala

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00307.2021 ◽

2021 ◽

Author(s):

Tian Yuan ◽

Albert Orock ◽

Beverley Greenwood-Van Meerveld

Keyword(s):

Chronic Stress ◽

Environmental Enrichment ◽

Visceral Pain ◽

Visceral Hypersensitivity ◽

Female Rats ◽

Central Nucleus ◽

Dorsal Margin ◽

Protective Effects ◽

Male And Female Rats ◽

Synaptic Pruning

Cognitive behavioral therapy (CBT) improves the quality of life for patients with brain-gut disorders, however, the underlying mechanisms of CBT remain to be explored. Previously we showed that environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, ameliorates chronic stress-induced visceral hypersensitivity in a rodent model via mechanisms involving altered activity in the central nucleus of amygdala (CeA). In the present study, we investigated whether microglia-mediated synaptic plasticity in the CeA is a potential mechanism underlying the protective effects of EE against stress-induced visceral hypersensitivity. We sterotaxically implanted corticosterone (CORT) micropellets onto the dorsal margin of the CeA shown previously to induce colonic hypersensitivity. Animals were housed in EE cages or standard cages for 14 days following CORT implantation. Visceral sensitivity was assessed via visceromotor behavioral response to colorectal distension. Microglial morphology, microglia-mediated synaptic engulfment and the expression of synaptic pruning-related signals C1q, C3 and C3R were measured using immunofluorescence and RNAscope assay. We found that housing CORT implanted rats in EE cages for 14 days attenuated visceral hypersensitivity in both male and female rats as compared to control rats maintained in standard housing. EE reduced CORT-induced microglial remodeling and microglia-mediated synaptic pruning with reduced C1q and CR3, but not C3, expression. Our data suggest that exposure to EE is sufficient to ameliorate stress-induced visceral pain via reducing amygdala microglia-modulated neuronal plasticity.

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Amygdalar Corticotropin-Releasing Factor Signaling Is Required for Later-Life Behavioral Dysfunction Following Neonatal Pain

Frontiers in Physiology ◽

10.3389/fphys.2021.660792 ◽

2021 ◽

Vol 12 ◽

Author(s):

Seth M. Davis ◽

Jared T. Zuke ◽

Mariah R. Berchulski ◽

Michael A. Burman

Keyword(s):

Receptor Antagonist ◽

Fear Conditioning ◽

Later Life ◽

Corticotropin Releasing Factor ◽

Female Rats ◽

Central Nucleus ◽

Neonatal Pain ◽

Stage Of Development ◽

Male And Female Rats ◽

Crf System

Neonatal pain such as that experienced by infants in the neonatal intensive care unit is known to produce later-life dysfunction including heightened pain sensitivity and anxiety, although the mechanisms remain unclear. Both chronic pain and stress in adult organisms are known to influence the corticotropin-releasing factor (CRF) system in the Central Nucleus of the Amygdala, making this system a likely candidate for changes following neonatal trauma. To examine this, neonatal rats were subjected to daily pain, non-painful handling or left undisturbed for the first week of life. Beginning on postnatal day, 24 male and female rats were subjected to a 4-day fear conditioning and sensory testing protocol. Some subjects received intra-amygdalar administration of either Vehicle, the CRF receptor 1 (CRF1) receptor antagonist Antalarmin, or the CRF receptor 2 (CRF2) receptor antagonist Astressin 2B prior to fear conditioning and somatosensory testing, while others had tissue collected following fear conditioning and CRF expression in the CeA and BLA was assessed using fluorescent in situ hybridization. CRF1 antagonism attenuated fear-induced hypersensitivity in neonatal pain and handled rats, while CRF2 antagonism produced a general antinociception. In addition, neonatal pain and handling produced a lateralized sex-dependent decrease in CRF expression, with males showing a diminished number of CRF-expressing cells in the right CeA and females showing a similar reduction in the number of CRF-expressing cells in the left BLA compared to undisturbed controls. These data show that the amygdalar CRF system is a likely target for alleviating dysfunction produced by early life trauma and that this system continues to play a major role in the lasting effects of such trauma into the juvenile stage of development.

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