Biology subjects

Boyt, K. M.

Publications and source records attributed to Boyt, K. M..

6 recordsLinked to original sources

bioRxiv2023

GABA Release From Central Amygdala Neurotensin Neurons Differentially Modulates Reward and Consummatory Behavior in Male and Female Mice

The central nucleus of the amygdala is known to play key roles in alcohol use and affect. Neurotensin neurons in the central nucleus of the amygdala have been shown to regulate alcohol drinking in male mice. However, little is known about which neurotransmitters released by these cells drive alcohol consumption or whether these cells drive alcohol consumption in female mice. Here we show that knockdown of GABA release from central amygdala neurotensin neurons using a Nts-cre-dependent vGAT-shRNA-based AAV strategy reduces alcohol drinking in male, but not female, mice. This manipulation did not impact avoidance behavior, except in a fasted novelty-suppressed feeding test, in which vGAT shRNA mice demonstrated increased latency to feed on a familiar high-value food reward, an effect driven by male mice. In contrast, vGAT shRNA female mice showed heightened sensitivity to thermal stimulation. These data show a role for GABA release from central amygdala neurotensin neurons in modulating consumption of rewarding substances in different motivational states.

neuroscience↗

bioRxiv2023

Dopamine D2 receptors in the bed nucleus of the stria terminalis modulate alcohol-related behaviors.

Dysregulation of the dopamine (DA) system is a hallmark of substance abuse disorders, including alcohol use disorder (AUD). Of the DA receptor subtypes, the DA D2 receptors (D2Rs) play a key role in the reinforcing effects of alcohol. D2Rs are expressed in numerous brain regions associated with the regulation of appetitive behaviors. One such region is the bed nucleus of the stria terminalis (BNST), which has been linked to the development and maintenance of AUD. Recently, we identified alcohol withdrawal-related neuroadaptations in the periaqueductal gray/dorsal raphe to BNST DA circuit in male mice. However, the role of D2R-expressing BNST neurons in voluntary alcohol consumption is not well characterized. In this study, we used a CRISPR-Cas9-based viral approach, to selectively reduce the expression of D2Rs in BNST VGAT neurons and interrogated the impact of BNST D2Rs in alcohol-related behaviors. In male mice, reduced D2R expression potentiated the stimulatory effects of alcohol and increased voluntary consumption of 20% w/v alcohol in a two-bottle choice intermittent access paradigm. This effect was not specific to alcohol, as D2R deletion also increased sucrose intake in male mice. Interestingly, cell-specific deletion of BNST D2Rs in female mice did not alter alcohol-related behaviors but lowered the threshold for mechanical pain sensitivity. Collectively, our findings suggest a role for postsynaptic BNST D2Rs in the modulation of sex-specific behavioral responses to alcohol and sucrose.

neuroscience↗

bioRxiv2023

Impact and role of hypothalamic corticotropin releasing hormone neurons in withdrawal from chronic alcohol consumption in female and male mice.

Worldwide, alcohol use and abuse are a leading risk of mortality, causing 5.3% of all deaths (W.H.O., 2022). The endocrine stress system, initiated by the peripheral release of corticotropin releasing hormone (CRH) from primarily glutamatergic neurons in the paraventricular nucleus of the hypothalamus (PVN), is profoundly linked with alcohol use, abuse, and relapse (Blaine & Sinha, 2017). These PVN CRH-releasing (PVNCRH) neurons are essential for peripheral and central stress responses (Rasiah et al., 2023), but little is known about how alcohol affects these neurons. Here, we show that two- bottle choice alcohol consumption blunts the endocrine mediated corticosterone response to stress during acute withdrawal in female mice. Conversely, using slice electrophysiology, we demonstrate that acute withdrawal engenders a hyperexcitable phenotype of PVNCRH neurons in females that is accompanied by increased glutamatergic transmission in both male and female mice. Only male mice show a concurrent increase in GABAergic synaptic transmission. We then tested whether chemogenetic inhibition of PVNCRH neurons would restore stress response in female mice with a history of alcohol drinking in the looming disc test, which mimics an approaching predator threat. Accordingly, inhibition of PVNCRH neurons reduced active escape in hM4Di alcohol history mice only. This study indicates that stress responsive PVNCRH neurons in females are particularly affected by a history of alcohol consumption. Interestingly, women have indicated an increase in heavy alcohol use to cope with stress (Rodriguez et al., 2020), perhaps pointing to a potential underlying mechanism in alcohol mediated changes to PVNCRH neurons that alter stress response.

neuroscience↗

bioRxiv2022

Sex-specific regulation of binge drinking and affective behaviors by subcortical serotonin 5HT2c receptors

Serotonin 5HT2c receptors have been implicated in the pathophysiology of both mood disorders and alcohol use disorder, but the circuits mediating the effects of systemic pharmacological manipulations of this receptor on behavior have not been identified. Binge alcohol consumption induces discrete social and arousal disturbances in human populations, which are thought to promote increased drinking. However, whether models of binge drinking in rodents can induce these same long-term negative behavioral symptoms is unknown. In this study, we employed multiple anatomical, physiological, and behavioral approaches to identify two populations of neurons expressing serotonin 5HT2c receptors, one in the lateral habenula (LHb5HT2c) and one in the bed nucleus of the stria terminalis (BNST5HT2c), that display coordinated in-vivo responses to social, arousal, and alcohol-related stimuli and are physiologically modulated by binge alcohol consumption in a sex-specific manner. Critically, these physiological changes were associated with sex-specific behavioral disturbances that closely mirror social and arousal symptoms observed in humans during abstinence from binge drinking. Specifically, we observed that one week of abstinence from three weeks of binge alcohol drinking induced social recognition deficits in females and potentiated acoustic startle responses in males. While both populations of neurons (BNST and LHb) and the 5HT2c receptor itself contribute to the sex-specific effects of alcohol on social and arousal behaviors to some degree, the primary causal mechanism underlying these phenomena appears to be excessive activation of LHb5HT2c neurons. These findings may have implications for the development of sex-specific treatments for mood and alcohol use disorders targeting the brains serotonin system.

neuroscience↗

bioRxiv2019

Kappa Opioid Receptor and Dynorphin Signaling in the Central Amygdala Regulates Alcohol Intake

Excessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes. However, it is unclear whether these effects are due to dynorphin or KOR arising from within the CeA itself or other input brain regions. To directly examine the role of preprodynorphin (PDYN) and KOR expression in CeA neurons, we performed region-specific conditional knockout of these genes and assessed the effects on the Drinking in the Dark (DID) and Intermittent Access (IA) paradigms. We then examined the effects of DID on PDYN and KOR modulation of CeA circuit physiology. Conditional gene knockout resulted in sex-specific responses wherein PDYN knockout decreased alcohol drinking in both male and female mice, whereas KOR knockout decreased drinking in males only. We also found that neither PDYN nor KOR knockout protected against anxiety caused by alcohol drinking. Lastly, a history of alcohol drinking did not alter synaptic transmission in PDYN neurons in the CeA of either sex, but excitability of PDYN neurons was increased in male mice only. Taken together, our findings indicate that PDYN and KOR signaling in the CeA plays an important role in regulating excessive alcohol consumption and highlight the need for future studies to examine how this is mediated through downstream effector regions.

neuroscience↗

bioRxiv2018

Stress-induced alterations of norepinephrine release in the bed nucleus of the stria terminalis of mice

Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine. Previous studies show that stress elevates norepinephrine levels in the bed nucleus of the stria terminalis (BNST), a critical node regulating anxiety and upstream of stress responses. Here, we use mice expressing channelrhodopsin in norepinephrine neurons to selectively activate terminals in the BNST, and measure norepinephrine release with fast-scan cyclic voltammetry. Mice exposed to a single restraint session show an identical norepinephrine release profile compared to that of unexposed mice. Mice experiencing five days of restraint stress, however, show elevated noradrenergic release across multiple stimulation parameters, and reduced sensitivity to the 2-adrenergic receptor antagonist idazoxan. These data are the first to examine norepinephrine release in the BNST to tonic and phasic stimulation frequencies, and confirm that repeated stress alters autoreceptor sensitivity.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR/small/335653_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@75ef4aorg.highwire.dtl.DTLVardef@b0fd27org.highwire.dtl.DTLVardef@1bc3afborg.highwire.dtl.DTLVardef@c469f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗