Biology subjects

Mahler, S. V.

Publications and source records attributed to Mahler, S. V..

13 recordsLinked to original sources

bioRxiv2025

Ventral Pallidum GABA Neuron Inhibition Augments Context-Appropriate Defensive Responses to Learned Threat Cues

The ventral pallidum (VP) is embedded within the brain circuits controlling motivated behavior, which are heavily implicated in addiction and other psychiatric disorders. Prior work showed that VP GABAergic neurons (VPGABA) promote reward approach and seeking, while the intermixed population of VP glutamate neurons instead promote avoidance and aversion. Some have thus suggested a functional dichotomy between these VP subpopulations in reward versus threat. We test this hypothesis by asking how inhibiting VPGABA impacts active and passive defensive responses to learned threat cues in the absence of rewards. We taught GAD1:Cre rats with inhibitory VPGABA DREADDs (or control rats) that a metal probe delivers shock, or that a 20sec auditory cue precedes footshocks. These stimuli thereafter elicit active defensive burying, or passive freezing responses, respectively. We found that VPGABA inhibition with CNO markedly increased stimulus-appropriate defensive responses to both types of learned threats, but failed to consistently alter new learning about them--suggesting VPGABA mediates aversive motivation but not memory formation. VPGABA inhibition also altered threat-related c-Fos expression within VP cell populations, and in their efferent target lateral habenula, but not mediodorsal thalamus--pointing to potential underlying circuit mechanisms of defensive responses. Results indicate that VPGABA neurons not only promote reward seeking as previously reported, but that they may also actively inhibit defensive responses to threats that might otherwise compete with reward seeking. This refines our understanding of subcortical valanced motivation circuits, and may suggest new targets for intervening in disorders like addiction and depression. Highlights-Inhibiting VPGABA increases defenses against threatening stimuli -Both active (burying) and passive (freezing) responses were enhanced -Inhibiting VPGABA excites other VP cells, and neurons in downstream LHb -VP subpopulations may interact to bidirectionally modulate circuits and adaptive behaviors Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/672918v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1978f03org.highwire.dtl.DTLVardef@12e4d59org.highwire.dtl.DTLVardef@d81bfforg.highwire.dtl.DTLVardef@164261_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Adolescent THC impacts on mPFC dopamine-mediated cognitive processes in male and female rats

RationaleAdolescent cannabis use is linked to later-life changes in cognition, learning, and memory. Rodent experimental studies suggest {Delta}9-tetrahydrocannabinol (THC) influences development of circuits underlying these processes, especially in the prefrontal cortex, which matures during adolescence. ObjectiveWe determined how 14 daily THC injections (5mg/kg) during adolescence persistently impacts medial prefrontal cortex (mPFC) dopamine-dependent cognition. MethodsIn adult Long Evans rats treated as adolescents with THC (AdoTHC), we quantify performance on two mPFC dopamine-dependent reward-based tasks--strategy set shifting and probabilistic discounting. We also determined how acute dopamine augmentation with amphetamine (0, 0.25, 0.5 mg/kg), or specific chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons and their projections to mPFC impacts probabilistic discounting. ResultsAdoTHC sex-dependently impacts acquisition of cue-guided instrumental reward seeking, but has minimal effects on set-shifting or probabilistic discounting in either sex. When we challenged dopamine circuits acutely with amphetamine during probabilistic discounting, we found reduced discounting of improbable reward options, with AdoTHC rats being more sensitive to these effects than controls. In contrast, neither acute chemogenetic stimulation of VTA dopamine neurons nor pathway-specific chemogenetic stimulation of their projection to mPFC impacted probabilistic discounting in control rats, although stimulation of this cortical dopamine projection slightly disrupted choices in AdoTHC rats. ConclusionsThese studies confirm a marked specificity in the cognitive processes impacted by AdoTHC exposure. They also suggest that some persistent AdoTHC effects may alter amphetamine-induced cognitive changes in a manner independent of VTA dopamine neurons or their projections to mPFC.

animal behavior and cognition↗

bioRxiv2023

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

RationaleDesigner receptors exclusively activated by designer drugs (DREADDs) are a tool for "remote control" of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, most commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist. ObjectivesSecond-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit. MethodsMale and female TH:Cre+ rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons in TH:Cre+ rats. Rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in a counterbalanced order. ResultsAll three CNO doses reduced operant food seeking in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest tested J60 dose significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre+ rats were correlated and were present in both sexes. ConclusionsFindings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.

neuroscience↗

bioRxiv2022

Long-term effects of THC exposure on reward learning and motivated behavior in adolescent and adult male rats

RationaleThe endocannabinoid system makes critical contributions to reward processing, motivation, and behavioral control. Repeated exposure to THC or other cannabinoid drugs can cause persistent adaptions in the endocannabinoid system and associated neural circuitry. It remains unclear how such treatments affect the way rewards are processed and pursued. Objective and methodsWe examined if repeated THC exposure (5 mg/kg/day for 14 days) during adolescence or adulthood led to long-term changes in rats capacity to flexibly encode and use action-outcome associations for goal-directed decision making. Effects on hedonic feeding and progressive ratio responding were also assessed. ResultsTHC exposure had no effect on rats ability to flexibly select actions following reward devaluation. However, instrumental contingency degradation learning, which involves avoiding an action that is unnecessary for reward delivery, was augmented in rats with a history of adult but not adolescent THC exposure. THC-exposed rats also displayed more vigorous instrumental behavior in this study, suggesting a motivational enhancement. A separate experiment found that while THC exposure had no effect on hedonic feeding behavior, it increased rats willingness to work for food on a progressive ratio schedule, an effect that was more pronounced when THC was administered to adults. Adolescent and adult THC exposure had opposing effects on the CB1-receptor dependence of progressive ratio performance, decreasing and increasing sensitivity to rimonabant-induced behavioral suppression, respectively. ConclusionsOur findings reveal that exposure to a translationally relevant THC exposure regimen induces long-lasting, age-dependent alterations in cognitive and motivational processes that regulate the pursuit of rewards.

neuroscience↗

bioRxiv2022

Stress-induced plasticity of a novel CRH GABA projection disrupts reward behaviors

Disrupted operations of the reward circuit are thought to underlie major emotional disorders including depression and drug abuse1-3. These disorders commonly arise following early life stress4,5; however, how stress early in life enduringly impacts reward circuit functions to promote disease remains unclear. Here, we discover and characterize a novel stress-sensitive reward-circuit projection connecting the basolateral amygdala (BLA) and nucleus accumbens (NAc) that co-expresses GABA and the stress-reactive neuropeptide corticotropin-releasing hormone (CRH). We then identify a crucial role for this projection in executing the disrupted reward behaviors provoked by early-life adversity (ELA): Chemogenetic and optogenetic stimulations of the CRHGABA BLA[->]NAc projection in typically reared mice suppressed several reward seeking behaviors, recapitulating deficits resulting from ELA and demonstrating a key contribution of this pathway in the normal operations of the reward circuit. Next, inhibition of the CRHGABA BLA[->]NAc projection in adult mice that experienced ELA restored typical reward behaviors in these mice, and, in contrast, had little effect in typically reared mice, indicating a selective ELA-induced maladaptive plasticity of this reward-circuit projection. We discover a novel, stress-sensitive, reward inhibiting projection from the BLA[->]NAc with unique molecular features, which may provide targets for intervention in disabling mental illnesses.

neuroscience↗

bioRxiv2022

Ventral pallidum GABA neurons bidirectionally control opioid relapse across rat behavioral models

Opioid addiction is a chronic, relapsing disorder. Whether addicted individuals are forced to abstain or they decide themselves to quit using drugs, relapse rates are high--especially upon encountering contexts and stimuli associated with prior opioid use. Rodents similarly show context- and cue-induced reinstatement of drug seeking following abstinence, and intriguingly, the neural circuits underlying these relapse-like behaviors differ when abstinence is involuntarily imposed, versus when animals decide themselves to cease taking drug. Here, we employ two complementary rat behavioral models of relapse-like behavior for the highly reinforcing opioid drug remifentanil, and asked whether GABAergic neurons in the ventral pallidum (VPGABA) control opioid seeking under these behavioral conditions. Specifically, we asked how chemogenetically stimulating VPGABA neurons with clozapine-N-oxide (CNO) influences the ability of contextual or discrete remifentanil-paired cues to reinstate drug seeking following either voluntary (punishment-induced; GroupPunish), or experimenter-imposed (extinction training; GroupExt) abstinence. In GroupPunish rats, we also chemogenetically inhibited VPGABA neurons, and examined spontaneous VP activity (Fos) during cued-reinstatement. In both GroupPunish and GroupExt rats, stimulating Gq-signaling in VPGABA neurons augmented remifentanil reinstatement in a cue- and context-dependent manner. Conversely, engaging inhibitory Gi-signaling in VPGABA neurons in GroupPunish suppressed cue-induced reinstatement, and additionally cue-triggered seeking was correlated with Fos in rostral, but not caudal VP. In contrast, neither stimulating nor inhibiting VPGABA neurons influenced unpunished remifentanil self-administration. We conclude that VPGABA neurons bidirectionally control opioid seeking regardless of the specific relapse model employed, highlighting their fundamental role in opioid relapse-like behavior across behavioral models, and potentially across species. HighlightsO_LIWe acutely inhibit or stimulate VP GABA neurons during opioid seeking C_LIO_LIVP GABA neurons mediate relapse-like behavior across behavioral models C_LIO_LIBehavioral context impacts DREADD stimulation of behavior, not VP activity C_LIO_LIRostral, not caudal VP Fos correlates with opioid reinstatement C_LI

neuroscience↗

bioRxiv2020

Ventral Pallidum GABA Neurons Mediate Motivation Underlying Risky Choice

Pursuing rewards while avoiding danger is an essential function of any nervous system. Here, we examine a new mechanism helping rats negotiate the balance between risk and reward when making high-stakes decisions. Specifically, we focus on GABA neurons within an emerging mesolimbic circuit nexus--the ventral pallidum (VP). These neurons play a distinct role from other VP neurons in simple motivated behaviors in mice, but their roles in more complex motivated behaviors is unknown. Here, we interrogate the behavioral functions of VPGABA neurons in male and female transgenic GAD1:Cre rats (and wildtype littermates), using a reversible chemogenetic inhibition approach. Employing a behavioral assay of risky decision making, and of the food-seeking and shock-avoidance components of this task, we show that engaging inhibitory Gi/o signaling specifically in VPGABA neurons suppresses motivation to pursue highly salient palatable foods, and possibly also motivation to avoid being shocked. In contrast, inhibiting these neurons did not affect seeking of low-value food, free consumption of palatable food, or unconditioned affective responses to shock. Accordingly, when rats considered whether to pursue food despite potential for shock in a risky decision-making task, inhibiting VPGABA neurons caused them to more readily select a small but safe reward over a large but dangerous one--an effect not seen in the absence of shock threat. Together, results indicate that VPGABA neurons are critical for high-stakes adaptive responding that is necessary for survival, but which may also malfunction in psychiatric disorders. Significance StatementIn a dynamic world, it is essential to implement appropriate behaviors under circumstances involving rewards, threats, or both. Here, we demonstrate a crucial role for VPGABA neurons in high-stakes motivated behavior of several types. We show that this VPGABA role in motivation impacts decision making, as inhibiting these neurons yields a conservative, risk-averse strategy not seen when the task is performed without threat of shock. These new roles for VPGABA neurons in behavior may inform future strategies for treating addiction, and other disorders of maladaptive decision making.

neuroscience↗

bioRxiv2019

On the origins of a selective vulnerability to opioid addiction.

The origins and neural bases of the current opioid addiction epidemic are unclear. Genetics plays a major role in addiction vulnerability, but cannot account for the recent exponential rise in opioid abuse, so environmental factors must contribute. Individuals with history of early-life adversity (ELA) are disproportionately prone to opioid addiction, yet whether ELA interacts with factors such as increased access to opioids to directly influence brain development and function and cause opioid addiction vulnerability is unknown. We simulated ELA in female rats and this led to a striking opioid addiction-like phenotype. This was characterized by resistance to extinction, increased relapse-like behavior, and, as in addicted humans, major increases in opioid economic demand. By contrast, seeking of a less salient natural reward was unaffected by ELA, whereas demand for highly palatable treats was augmented. These discoveries provide novel insights into the origins and nature of reward circuit malfunction that may set the stage for addiction.

neuroscience↗

bioRxiv2019

Ventral Pallidum is Essential for Cocaine Reinstatement After Voluntary Abstinence

Addiction is a chronic relapsing disorder, and during recovery many people experience several relapse events as they attempt to voluntarily abstain from drug. New preclinical relapse models have emerged which capture this common human experience of relapse after voluntary abstinence, and mounting evidence indicates that reinstatement of drug seeking after voluntary abstinence recruits neural circuits distinct from reinstatement following experimenter-imposed abstinence, or abstinence due to extinction training. Ventral pallidum (VP), a key limbic node involved in drug seeking, has well-established roles in conventional reinstatement models tested following extinction training, but it is unclear whether this region also participates in more translationally-relevant models of relapse. Here we show that chemogenetic inhibition of VP neurons strongly attenuates cocaine-, context-, and cue-induced reinstatement tested after voluntary, punishment-induced abstinence. This effect was strongest in the most compulsive, punishment-resistant rats, and reinstatement was associated with neural activity in anatomically-defined VP subregions. VP inhibition also attenuated the propensity of rats to display hesitations, a risk assessment behavior seen during punished drug taking that is likely due to concurrent approach and avoidance motivations. These results indicate that VP, unlike other connected limbic brain regions, is essential for reinstatement of drug seeking after voluntary abstinence. Since VP inhibition effects were strongest in the most compulsively cocaine-seeking individuals, this could indicate that VP plays a particularly important role in the most pathological, addiction-like behavior, making it an attractive target for future therapeutic interventions.

neuroscience↗

bioRxiv2018

Prefrontal pathways provide top down control of memory for sequences of events

We remember our lives as sequences of events, but it is unclear how these memories are controlled during retrieval. In rats, prelimbic cortex (PL) is positioned to influence sequence memory through extensive top down inputs to the nucleus reuniens of the thalamus (RE) and perirhinal cortex (PER), regions heavily interconnected with the hippocampus. Here, we tested the hypothesis that specific PLRE and PLPER projections regulate sequence memory retrieval using an hM4Di synaptic-silencing approach. First, we show that the suppression of PL activity impairs sequence memory. Second, we show that inhibiting PLRE and PLPER pathways effectively eliminated sequence memory. Last, we performed a sequential lag analysis showing that the PLRE pathway contributes to a working memory retrieval strategy, and the PLPER pathway contributes to a temporal context memory retrieval strategy. These results demonstrate that the PLRE and PLPER pathways serve as top down mechanisms that control sequence memory retrieval strategies.

neuroscience↗

bioRxiv2018

Chemogenetic ligands for translational neurotheranostics

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for precision medicine-based clinical theranostics. DREADD ligands developed to date are not appropriate for such translational applications. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine. The second-generation DREADD agonist, Compound 21 (C21), was developed to overcome these limitations. We found that C21 has low brain penetrance, weak affinity, and low in vivo DREADD occupancy. To address these drawbacks, we developed two new DREADD agonists, JHU37152 and JHU37160, and the first dedicated positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons and at their long-range projections, enabling for the first time, noninvasive and longitudinal neuronal projection mapping and potential for neurotheranostic applications.

neuroscience↗

bioRxiv2018

Chemogenetic inhibition of ventral tegmental area dopamine neurons or their inputs to the nucleus accumbens disrupts cue-triggered reward seeking but not reward taking

Reward-paired cues stimulate reward-seeking behavior through a combination of motivational and cognitive processes. We used pathway-specific chemogenetic inhibition of dopamine neurons to determine their role in the cue-elicited reward seeking, and applied a novel analytic approach to assay cue-induced changes in reward expectancy. Inhibiting ventral tegmental area dopamine neurons abolished cue-induced reward seeking but not reward retrieval, indicating that this pathway modulates response vigor but not reward expectancy. Locally inhibiting dopamine inputs to nucleus accumbens also disrupted cue-elicited reward seeking but not retrieval. Interestingly, the suppression produced by this treatment was greater in rats that responded to cues with exploratory reward seeking, without attempting to retrieve reward, than in rats exhibiting complete bouts of seeking with retrieval, indicating that individuals differ in their reliance on a dopamine-mediated motivational process. These findings shed new light on the behavioral and neural mechanisms of adaptive and compulsive forms of cue-motivated behavior.

neuroscience↗

bioRxiv2018

Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaines reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered cue-induced cocaine seeking strategy, but not the motivational impact of cocaine cues per se. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling, and DA neuron efferent target, highlighting their multifaceted roles in addiction.\n\nSignificance StatementG-protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how metabotropic signaling impacts dopamines complex roles in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq- and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling altered the response strategy employed during cued reinstatement, and reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and indicate potential new approaches for intervening in these processes to treat addiction.

neuroscience↗