Biology subjects

Pati, D.

Publications and source records attributed to Pati, D..

11 recordsLinked to original sources

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

Disentangling the effects of Corticotrophin Releasing Factor and GABA release from the ventral bed nucleus of the stria terminalis on ethanol self-administration in mice

Excessive alcohol use causes a great deal of harm and negative health outcomes. Corticotrophin releasing factor (CRF), a stress-related neuropeptide, has been implicated in binge ethanol intake and ethanol dependence. CRF containing neurons in the bed nucleus of the stria terminalis (BNSTCRF) can control ethanol consumption. These BNSTCRF neurons also release GABA, raising the question, is it CRF or GABA release or both that is controlling alcohol consumption. Here, we used viral vectors to separate the effects of CRF and GABA release from BNSTCRF neurons on the escalation of ethanol intake in an operant self-administration paradigm in male and female mice. We found that CRF deletion in BNST neurons reduces ethanol intake in both sexes, with a stronger effect in males. For sucrose self-administration there was no effect of CRF deletion. Suppression of GABA release, via knockdown of vGAT, from BNSTCRF produced a transient increase in ethanol operant self-administration following in male mice, and reduced in motivation to work for sucrose on a progressive ratio schedule of reinforcement in a sex-dependent manner. Together, these results highlight how different signaling molecules from the same populations of neurons can bidirectionally control behavior. Moreover, they suggest that BNST CRF release is important for high intensity ethanol drinking that precedes dependence, whereas GABA release from these neurons may play a role in regulating motivation.

neuroscience↗

bioRxiv2022

A monotone single index model for missing-at-random longitudinal proportion data

Beta distributions are commonly used to model proportion valued response variables, commonly encountered in longitudinal studies. In this article, we develop semi-parametric Beta regression models for proportion valued responses, where the aggregate covariate effect is summarized and flexibly modeled, using a interpretable monotone time-varying single index transform of a linear combination of the potential covariates. We utilize the potential of single index models, which are effective dimension reduction tools and accommodate link function misspecification in generalized linear mixed models. Our Bayesian methodology incorporates the missing-at-random feature of the proportion response, and utilize Hamiltonian Monte Carlo sampling to conduct inference. We explore finite-sample frequentist properties of our estimates, and assess the robustness via detailed simulation studies. Finally, we illustrate our methodology via application to a motivating longitudinal dataset on obesity research recording proportion body fat.

developmental biology↗

bioRxiv2021

Delineation of dynorphin and kappa opioid receptor circuit elements in alcohol consumption

Alcohol use disorder is complex and multi-faceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated that both the insular cortex and dynorphin (DYN)/Kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit components on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knockout strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact sucrose intake. Further, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA in male mice only. Alcohol consumption was not affected by insula KOR knockout in either sex. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPN) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPN. Combined, our findings suggest there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR microcircuitry. Significance StatementThe insular cortex is a complex region that serves as an integratory hub for sensory inputs. In our previous work, we identified a microcircuit in the insula that signals through the kappa opioid receptor (KOR) and its endogenous ligand dynorphin (DYN). Both the insula and DYN/KOR systems have been implicated in excessive alcohol use and alcohol use disorder (AUD). Here, we utilize converging approaches to determine how insula DYN/KOR microcircuit components contribute to escalated alcohol consumption. Our findings show that insula DYN/KOR systems regulate distinct phases of alcohol consumption in a sex-specific manner, which may contribute to the progression to AUD.

neuroscience↗

bioRxiv2021

Tumor necrosis factor-α modulates GABAergic and Dopaminergic neurons in the ventral periaqueductal gray of female mice.

Neuroimmune signaling is increasingly identified as a critical component of various illnesses, including chronic pain, substance use disorder, and depression. However, the underlying neural mechanisms remain unclear. Proinflammatory cytokines, such as tumor necrosis factor- (TNF-), may play a key role by modulating synaptic function and long-term plasticity. The midbrain structure periaqueductal gray (PAG) plays a well-established role in pain processing, and while TNF- inhibitors have emerged as a potential therapeutic strategy for pain-related disorders, the impact of TNF- on PAG neuronal activity has not been thoroughly characterized. Recent studies have identified subpopulations of ventral PAG (vPAG) with opposing effects on nociception, with DA neurons driving pain relief in contrast to GABA neurons. Therefore, we used ex vivo slice physiology to examine the effects of TNF- on neuronal activity of both subpopulations. We selectively targeted GABA and dopamine neurons using a vGAT-reporter and a TH-eGFP reporter mouse line, respectively. Following exposure to TNF-, the intrinsic properties of GABA neurons were altered, resulting in increased excitability along with a reduction in glutamatergic synaptic drive. In DA neurons, TNF- exposure resulted in a robust decrease in excitability along with a modest reduction in glutamatergic synaptic transmission. Furthermore, the effect of TNF- was specific to excitatory transmission onto DA neurons as inhibitory transmission was unaltered. Collectively, these data suggest that TNF- differentially affects the basal synaptic properties of GABA and DA neurons and enhances our understanding of how TNF- mediated signaling modulates vPAG function. New & NoteworthyThe present study describes the effects of tumor necrosis factor- (TNF-) on two distinct subpopulations of neurons in the ventral periaqueductal gray (vPAG). We show that TNF- alters both neuronal excitability and glutamatergic synaptic transmission on GABA neurons and dopamine neurons within the vPAG. This provides critical new information on the role of TNF- in the potential modulation of pain since activation of vPAG GABA neurons drives nociception, whereas activation of DA neurons drives analgesia.

neuroscience↗

bioRxiv2020

Activation of the kappa opioid receptor / dynorphin system alters stress and threat responding during acute withdrawal from intermittent alcohol drinking in male mice.

The dynorphin/kappa opioid receptor (KOR) system in the brain regulates both stressful experiences and negative, aversive states during withdrawal from drugs of abuse. We explored the role of this system during acute withdrawal from long-term alcohol drinking. Male C57BL/6J mice were subjected to repeated forced swim tests, home cage exposure to a predator odor, and a visual threat after intermittent access to alcohol or water. Systemic injection of KOR antagonist norBNI reversed alcohol-related differences in immobility time during the second swim test and reduced burying behavior in response to predator odor, but did not affect behavioral response to visual threat. HighlightsO_LIIntermittent alcohol drinking changed stress reactions in mice. C_LIO_LIKOR antagonist norBNI altered some, but not all, stress responses in alcohol drinkers C_LI

neuroscience↗

bioRxiv2019

Endogenous oxytocin inhibits hypothalamic stress responsive neurons following acute hypernatremia

Significant prior evidence indicates that centrally acting oxytocin robustly modulates stress responsiveness and anxiety-like behavior, although the neural mechanisms behind these effects are not completely understood. A plausible neural basis for oxytocin mediated stress reduction is via inhibition of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) that regulate activation of the hypothalamic-pituitary-adrenal (HPA) axis. Previously, we have shown that following subcutaneous injection of 2.0 M NaCl, oxytocin (OT) synthesizing neurons are activated in the rat PVN, an oxytocin receptor (Oxtr) dependent inhibitory tone develops on a subset of parvocellular neurons, and stress-mediated increases in plasma corticosterone levels are blunted. Here, we utilized transgenic male CRH-reporter mice to selectively target PVN CRH neurons for whole-cell recordings. These experiments reveal that acute salt loading produces tonic inhibition of PVN CRH neurons through a mechanism that is largely independent of synaptic activity. Further studies reveal that CRH neurons within the PVN synthesize mRNA for Oxtr(s). Salt induced Oxtr-dependent inhibitory tone was eliminated in individual PVN CRH neurons filled with GDP-{beta}-S, and was also largely absent in PVN CRH neurons extracted form CRH-Oxtr KO mice. Additional electrophysiological studies suggest that reduced excitability of PVN CRH neurons in salt loaded animals is associated with increased activation of an inwardly rectifying potassium channel. Collectively, these data reveal a likely cellular mechanism by which endogenous oxytocin signaling reduces the excitability of PVN CRH neurons to curb stress responsiveness during times of high plasma osmolality.

neuroscience↗

bioRxiv2019

Ethanol-induced conditioned place preference and aversion differentially alter plasticity in the bed nucleus of stria terminalis

Contextual cues associated with drugs of abuse, such as ethanol, can trigger craving and drug seeking behavior. Pavlovian procedures, such as place conditioning, have been widely used to study the rewarding/aversive properties of drugs and the association between environmental cues and drug seeking. Previous research has shown that ethanol as an unconditioned stimulus can induce a strong conditioned place preference (CPP) or aversion (CPA) in rodents. However, the neural mechanisms underlying ethanol induced reward and aversion have not been thoroughly investigated. The bed nucleus of the stria terminalis (BNST), an integral part of the extended amygdala, is engaged by both rewarding and aversive stimuli and plays a role in ethanol seeking behavior. Here, we used ex-vivo slice physiology to probe learning-induced synaptic plasticity in the BNST following ethanol-induced CPP and CPA. Male DBA/2J mice (2-3 months old) were conditioned using previously reported ethanol-induced CPP/CPA procedures. Ethanol-induced CPP was associated with increased neuronal excitability in the ventral BNST (vBNST). Conversely, ethanol-induced CPA resulted in a significant decrease in spontaneous glutamatergic transmission without alterations in GABAergic signaling. Ethanol-CPA also led to significant increase in paired pulse ratio at excitatory synapses, suggestive of a decrease in presynaptic glutamate release. Collectively, these data demonstrate that the vBNST is involved in the modulation of contextual learning associated with both the rewarding and the aversive properties of ethanol in mice.

neuroscience↗

bioRxiv2018

Male and female mice demonstrate divergent cellular responses in the bed nucleus of stria terminalis (BNST) following morphine withdrawal

The United States is experiencing an opioid epidemic of significant proportions, imposing enormous fiscal and societal costs. While prescription opioid analgesics are essential for treating pain, the cessation of these drugs can induce a withdrawal syndrome, and thus opioid use often persists to alleviate or avoid these symptoms. Therefore, it is essential to understand the neurobiology underlying this critical window of withdrawal from opioid analgesics to prevent continued usage. To model this, we administered a low dose of morphine, and precipitated withdrawal with naloxone to investigate the behavioral and cellular responses in C57BL/6J male and female mice. Following 3 days of administration, both male and female mice sensitized to the repeated bouts of withdrawal, as evidenced by their composite global withdrawal score. Female mice exhibited increased withdrawal symptoms on some individual measures, but did not show characteristic weight loss observed in male mice. Because of its role in mediating withdrawal-associated behaviors, we examined neuronal excitability and inhibitory synaptic transmission in the bed nucleus of the stria terminalis (BNST) 24 hours following the final precipitated withdrawal. In male mice, morphine withdrawal increased spontaneous GABAergic signaling compared to controls. In contrast, morphine withdrawal decreased spontaneous GABAergic signaling, and increased BNST projection neuron excitability in female mice. Intriguingly, these opposing GABAergic effects were dependent on within slice excitability. Our findings suggest that male and female mice manifest divergent cellular responses in the BNST following morphine withdrawal, and alterations in BNST inhibitory signaling may be a significant factor contributing to the expression of behaviors following opioid withdrawal.

neuroscience↗

bioRxiv2018

Predator odor increases glutamatergic synaptic transmission in the prelimbic cortex via corticotropin-releasing factor receptor 1 signaling

The authors have withdrawn their manuscript because the University of North Carolina at Chapel Hill conducted a research misconduct proceeding and concluded that research misconduct occurred involving results presented in this preprint. Hence, the results and conclusions of the preprint article are no longer reliable. The published version of this preprint (Neuropsychopharmacology, doi: 10.1038/s41386-018-0279-2) is being retracted as well. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

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↗