Biology subjects

Farrell, M. R.

Publications and source records attributed to Farrell, M. R..

5 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↗

bioRxiv2025

Trophic Transfer of Perfluoroalkyl Acids in a Periphyton-Mayfly-Zebrafish Food Chain

Per-and polyfluoroalkyl substances (PFAS) are ubiquitous contaminants in freshwater ecosystems. Many PFAS are incorporated into food webs, with potential effects on ecological and human health. However, PFAS incorporation into the base of aquatic food webs remains poorly understood. The goal of this study was to quantify the uptake and trophic transfer of both legacy and current use PFAS compounds using a simulated freshwater food chain in a lab setting. Natural periphytic biofilms were placed into trays containing equimolar binary aqueous PFAS mixtures at environmentally relevant concentrations for five days. Following the initial exposure period, newly hatched mayfly larvae were introduced into each tray to feed on periphyton for most of their larval development. The mature larvae were then fed to zebrafish. All water and biota samples contained detectable levels of the tested PFAS. All PFAS were more concentrated in periphyton than in water, and four of six PFAS were further concentrated in mayfly larvae relative to periphyton. PFDA was the most accumulative in all biota. PFAS concentrations in zebrafish were significantly correlated with those in larval mayflies. Assimilation efficiencies in zebrafish were high (>70%) for all compounds. Bioaccumulation of PFAS in periphyton and mayflies was positively correlated with log KOW and number of carbons.

ecology↗

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

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↗