Biology subjects

Prevost, E. D.

Publications and source records attributed to Prevost, E. D..

7 recordsLinked to original sources

bioRxiv2025

Untangling dopamine and glutamate in the ventral tegmental area

Ventral tegmental area (VTA) dopamine neurons are of great interest for their central roles in motivation, learning, and psychiatric disorders. While hypotheses of VTA dopamine neuron function posit a homogenous role in behavior (e.g., prediction error), they do not account for molecular heterogeneity. We find that glutamate-dopamine, nonglutamate-dopamine, and glutamate-only neurons are dissociable in their signaling of reward and aversion-related stimuli, prediction error, and electrical properties. In addition, glutamate-dopamine and nonglutamate-dopamine neurons differ in dopamine release dynamics. Aversion-related recordings of all dopamine neurons (not considering glutamate co-transmission) showed a mixed response that obscured dopamine subpopulation function. Within glutamate-dopamine neurons, glutamate and dopamine release had dissociable contributions toward reward and aversion-based learning and performance. Based on our results, we propose a new hypothesis on VTA dopamine neuron function: that dopamine neuron signaling patterns and their roles in motivated behavior depend on whether or not they co-transmit dopamine with glutamate.

neuroscience↗

bioRxiv2025

VGluT3 BNST neurons transmit GABA and restrict feeding without affecting rewarding or aversive processing

The bed nucleus of the stria terminalis (BNST) is involved in feeding, reward, aversion, and anxiety-like behavior. We identify BNST neurons defined by the expression of vesicular glutamate transporter 3, VGluT3. VGluT3 neurons were localized to anteromedial BNST, were molecularly distinct from accumbal VGluT3 neurons, and co-express vesicular GABA transporter (VGaT). Cell-type specific presynaptic processes were identified in arcuate nucleus (ARC) and the paraventricular nucleus of the hypothalamus (PVN), regions critical for feeding and homeostatic regulation. Whole-cell patch-clamp electrophysiology revealed that, while these neurons co-express VGluT3 and VGaT, they functionally transmit GABA to both ARC and PVN, with rare glutamate co-transmission to ARC. Neuronal recordings of VGluT3 BNST neurons showed greater calcium-dependent signaling in response to sucrose consumption while sated compared with fasted. When fasted, optogenetic stimulation of BNST VGluT3 neurons decreased sucrose consumption using several stimulation conditions but not when stimulation occurred prior to sucrose access, suggesting that BNST VGluT3 activation concurrent with consumption in the fasted state reduces feeding. BNST VGluT3 activation during anxiety-like paradigms (novelty-suppressed feeding, open field, and elevated zero maze) and real-time place conditioning resulted in no changes in anxiety-like or reward/aversion behavior. We interpret these data such that VGluT3 BNST neurons represent a unique cellular population within the BNST that provides inhibitory input to hypothalamic regions to decrease feeding without affecting anxiety-like or reward/aversion behavior.

neuroscience↗

bioRxiv2025

Assessing the role of BNST GABA neurons in backward conditioned suppression

Conditioned suppression is a useful paradigm for measuring learned avoidance. In most conditioned suppression studies, forward conditioning is used where a cue predicts an aversive stimulus. However, backward conditioning, in which an aversive stimulus predicts a cue, provides unique insights into learned avoidance due to its influence on both conditioned excitation and inhibition. We trained mice to consume sucrose in context A, associated an aversive stimulus in context B to few or many forward or backwards paired cues (CS+), and then tested for conditioned suppression in context A in response to the CS+. We found that few or many forward CS+ and few backward CS+ produced conditioned suppression, but many backwards cues did not. Administration of diazepam, a positive allosteric modulator of the GABA-A receptor, prevented conditioned suppression to the backward CS+ but not to the forward CS+. Furthermore, freezing behavior was observed in response to the forward CS+ but not the backward CS+, and diazepam had no effect on freezing or locomotion. We next examined BNST GABA neurons for potential sensitivity to backwards cues and conditioned suppression. VGaT BNST signaling increased in response to sucrose licks during the backward CS+ but not to licks outside the CS+ and not to the backward CS+ onset or offset. Using designer receptors, we found that BNST VGaT neuron activation, but not its inhibition, prevented backward conditioned suppression expression. We conclude that backward conditioned suppression is dependent on both positive allosteric modulation of GABA on GABA-A receptors by diazepam and BNST GABA neurons.

neuroscience↗

bioRxiv2024

Salience signaling and stimulus scaling of ventral tegmental area glutamate neuron subtypes

Ventral tegmental area (VTA) glutamatergic neurons participate in reward, aversion, drug-seeking, and stress. Subsets of VTA VGluT2+ neurons are capable of co-transmitting glutamate and GABA (VGluT2+VGaT+ neurons), transmitting glutamate without GABA (VGluT2+VGaT- neurons), or co-transmitting glutamate and dopamine (VGluT2+TH+ neurons), but whether these molecularly distinct subpopulations show behavior-related differences is not wholly understood. We identified that neuronal activity of each VGluT2+ subpopulation is sensitive to reward value but signaled this in different ways. The phasic maximum activity of VGluT2+VGaT+ neurons increased with sucrose concentration, whereas VGluT2+VGaT- neurons increased maximum and sustained activity with sucrose concentration, and VGluT2+TH+ neurons increased sustained but not maximum activity with sucrose concentration. Additionally, VGluT2+ subpopulations signaled consummatory preferences in different ways. VGluT2+VGaT- neurons and VGluT2+TH+ neurons showed a signaling preference for a behaviorally-preferred fat reward over sucrose, but in temporally-distinct ways. In contrast, VGluT2+VGaT+ neurons uniquely signaled a less behaviorally-preferred sucrose reward compared with fat. Further experiments suggested that VGluT2+VGaT+ consummatory reward-related activity was related to sweetness, partially modulated by hunger state, and not dependent on caloric content or behavioral preference. All VGluT2+ subtypes increased neuronal activity following aversive stimuli but VGluT2+VGaT+ neurons uniquely scaled their magnitude and sustained activity with footshock intensity. Optogenetic activation of VGluT2+VGaT+ neurons during low intensity footshock enhanced fear-related behavior without inducing place preference or aversion. We interpret these data such that VTA glutamatergic subpopulations signal different elements of rewarding and aversive experiences and highlight the unique role of VTA VGluT2+VGaT+ neurons in enhancing the salience of behavioral experiences.

neuroscience↗

bioRxiv2023

Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons

A unique population of ventral tegmental area (VTA) neurons co-transmits glutamate and GABA as well as functionally signals rewarding and aversive outcomes. However, the circuit inputs to VTA VGluT2+VGaT+ neurons are unknown, limiting our understanding of the functional capabilities of these neurons. To identify the inputs to VTA VGluT2+VGaT+ neurons, we coupled monosynaptic rabies tracing with intersectional genetic targeting of VTA VGluT2+VGaT+ neurons in mice. We found that VTA VGluT2+VGaT+ neurons received diverse brain-wide inputs. The largest numbers of monosynaptic inputs to VTA VGluT2+VGaT+ neurons were from superior colliculus, lateral hypothalamus, midbrain reticular nucleus, and periaqueductal gray, whereas the densest inputs relative to brain region volume were from dorsal raphe nucleus, lateral habenula, and ventral tegmental area. Based on these and prior data, we hypothesized that lateral hypothalamus and superior colliculus inputs were glutamatergic neurons. Optical activation of glutamatergic lateral hypothalamus neurons robustly activated VTA VGluT2+VGaT+ neurons regardless of stimulation frequency and resulted in flee-like ambulatory behavior. In contrast, optical activation of glutamatergic superior colliculus neurons activated VTA VGluT2+VGaT+ neurons for a brief period of time at high stimulation frequency and resulted in head rotation and arrested ambulatory behavior (freezing). For both pathways, behaviors induced by stimulation were uncorrelated with VTA VGluT2+VGaT+ neuron activity. However, stimulation of glutamatergic lateral hypothalamus neurons, but not glutamatergic superior colliculus neurons, was associated with VTA VGluT2+VGaT+ footshock-induced activity. We interpret these results such that inputs to VTA VGluT2+VGaT+ neurons may integrate diverse signals related to the detection and processing of motivationally-salient outcomes. Further, VTA VGluT2+VGaT+ neurons may signal threat-related outcomes, possibly via input from lateral hypothalamus glutamate neurons, but not threat-induced behavioral kinematics.

neuroscience↗

bioRxiv2023

Bed Nucleus of the Stria Terminalis GABA neurons are necessary for changes in foraging behavior following an innate threat

Foraging is a universal behavior that has co-evolved with predation pressure. We investigated the role of bed nucleus of the stria terminalis (BNST) GABA neurons in robotic and live predator threat processing and their consequences in post-threat encounter foraging. Mice were trained to procure food in a laboratory-based foraging apparatus in which food pellets were placed at discrete and incrementally greater distances from a nest zone. After mice learned to forage, they were exposed to either a robotic or live predator threat, while BNST GABA neurons were chemogenetically inhibited. Post-robotic threat encounter, mice spent more time in the nest zone, but other foraging parameters were unchanged compared to pre-encounter behavior. Inhibition of BNST GABA neurons had no effect on foraging behavior post-robotic threat encounter. Following live predator exposure, control mice spent significantly more time in the nest zone, increased their latency to successfully forage, and their overall foraging performance was significantly a ltered. I nhibition o f BNST GABA neurons during live predator exposure prevented changes in foraging behavior from developing after live predator threat. BNST GABA neuron inhibition did not alter foraging behavior during robotic or live predator threat. We conclude that while both robotic and live predator encounter effectively intrude on foraging behavior, the perceived risk and behavioral consequence of the threats are distinguishable. Additionally, BNST GABA neurons may play a role in the integration of prior innate predator threat experience that results in hypervigilance during post-encounter foraging behavior.

neuroscience↗

bioRxiv2022

Ventral Tegmental Area Glutamate Neurons establish a mu-opioid receptor gated circuit to mesolimbic dopamine neurons and regulate prescription opioid-seeking behavior

A two-neuron model of ventral tegmental area (VTA) opioid function classically involves VTA GABA neuron regulation of VTA dopamine neurons via a mu-opioid receptor dependent inhibitory circuit. However, this model predates the discovery of a third major type of neuron in the VTA: glutamatergic neurons. We find that about one-quarter of VTA neurons expressing the mu-opioid receptor are glutamate neurons without molecular markers of GABA co-release. Glutamate-Mu opioid receptor neurons are topographically distributed in the anterior VTA. The majority of remaining VTA mu-opioid receptor neurons are GABAergic neurons that are largely within the posterior VTA and do not express molecular markers of glutamate co-release. Optogenetic stimulation of VTA glutamate neurons results in monosynaptic excitatory currents recorded from VTA dopamine neurons that are reduced by presynaptic activation of the mu-opioid receptor ex vivo, establishing a local mu-opioid receptor dependent excitatory circuit from VTA glutamate neurons to VTA dopamine neurons. This VTA glutamate to VTA dopamine pathway regulates dopamine release to the nucleus accumbens through mu-opioid receptor activity in vivo. Behaviorally, VTA glutamate calcium-related neuronal activity increased following oxycodone consumption and response-contingent oxycodone-associated cues during self-administration and abstinent reinstatement of drug-seeking behavior. Further, chemogenetic inhibition of VTA glutamate neurons reduced abstinent oxycodone-seeking behavior in male but not female mice. These results establish 1) a three-neuron model of VTA opioid function involving a mu-opioid receptor gated VTA glutamate neuron pathway to VTA dopamine neurons that controls dopamine release within the nucleus accumbens, and 2) that VTA glutamate neurons participate in prescription opioid-seeking behavior.

neuroscience↗