Biology subjects

Frazier, C. J.

Publications and source records attributed to Frazier, C. J..

9 recordsLinked to original sources

bioRxiv2026

Ventral tegmental area dopamine neuron activity mediates multi-valent outcomes during decision making under risk of punishment

Dopamine contributes to reward-related decision making, but its contributions to decision contexts that include explicit punishment are less well understood. To elucidate the role of ventral tegmental area (VTA) dopamine neurons in decision making under risk of punishment, we used fiber photometry to record activity in these neurons during a decision-making task in which rats choose between a small, "safe" reward and a large reward associated with varying probabilities of explicit punishment. Dopamine neuron activity exhibited phasic increases during risky "Wins" (reward without punishment) and phasic decreases during risky "Losses" (reward plus punishment), each of which scaled with punishment probability and intensity. Further analyses revealed that this outcome-evoked activity predicted choices on subsequent trials. To determine whether VTA dopamine neuron activity plays a causal role in these risk-based decisions, we used optogenetics to selectively inhibit these neurons during risky Wins and Losses. Inhibition of VTA dopamine neurons during Wins selectively reduced the frequency of risky choices after a Win, whereas inhibition during Losses selectively reduced the frequency of risky choices after a Loss. These data reveal that VTA dopamine neuron activity during outcome receipt is causally related to subsequent decision-making behavior. In addition, the fact that the effects of inhibition on choice behavior were specific to the outcome with which the inhibition was paired suggests that VTA dopamine neuron activity contributes to updating after Wins and Losses independently. Significance StatementDopamine is implicated in movement, motivation, and learning, and has been strongly linked with substance use and risk-seeking behavior. Despite these associations, it is unclear how the activity of dopamine neurons influences decision making under risk of punishment. To elucidate this, we recorded from ventral tegmental area (VTA) dopamine neurons and found that their activity at the population level integrates reward alongside the probability and intensity of punishment experienced during risky outcomes. Further, inhibition of VTA dopamine neuron activity during risky outcomes decreased risk-seeking behavior in an outcome-specific manner. Our findings align with models suggesting that VTA dopamine neurons signal prediction errors, and provide insight into the role of these neurons in adaptive decision making.

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bioRxiv2025

Optogenetic inhibition reveals distinct contributions of medial prefrontal cortex to intertemporal choice in young and aged rats

The ability to choose adaptively between rewards differing in magnitude and delay (intertemporal choice) is critical for numerous life outcomes. Compared to younger adults, older adults tend to exhibit greater preference for large, delayed over small, immediate rewards (i.e., less delay discounting), which could lead to missed opportunities to obtain resources necessary for quality of life. Intertemporal choice is mediated by the prefrontal cortex, but how this is impacted by advanced age is not well understood. We used optogenetic inactivation to investigate contributions of medial prefrontal cortex (mPFC) during distinct components of an intertemporal choice task in young and aged rats. mPFC inactivation during deliberation (during decisions between small, immediate vs. large, delayed rewards) increased preference for large, delayed rewards in both age groups. In contrast, inactivation during delays prior to large reward delivery increased preference for large, delayed rewards only in aged rats. Choices were unaffected by inactivation during other task phases. Results suggest that mPFC integrates information regarding anticipated outcomes into the decision process across the whole lifespan, but that only in aging is mPFC critical for consolidating information regarding reward delays into the decision structure in order to modulate choice behavior.

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bioRxiv2025

Muscarinic type 1 receptor activated effectors in principal neurons of the rat basolateral amygdala

The basolateral amygdala (BLA) plays a crucial role in context-specific learning and memory by integrating valence-specific stimuli with internal physiological states. Cholinergic signaling systems modulate neural excitability to influence information processing in the BLA. Muscarinic acetylcholine receptors (mAChRs) are of particular interest because aberrant mAChR signaling in BLA circuits is associated with neuropsychiatric disorders, cognitive impairment, substance use, and age-related cognitive decline. This study evaluates mAChR activation in BLA principal neurons (PNs) in juvenile rat brain slices using whole-cell patch-clamp recordings. We found that bath application of carbachol (CCh,) produces a pirenzepine sensitive excitatory response in BLA PNs voltage clamped near the resting potential, which depends on an underlying biphasic change in membrane resistance, indicating an involvement of multiple effectors. More specifically, we observed that CCh excites BLA PNs by inhibiting the afterhyperpolarization (AHP), by reducing a steady state inhibitory current, and by promoting an afterdepolarization (ADP). We further identify and characterize a CCh-induced and calcium-activated non-selective cation current (ICAN) that underlies the ADP in voltage clamp. Overall, our findings provide new insights into specific effectors modulated by activation of pirenzepine sensitive mAChRs expressed by BLA PNs. We also reveal new details about the time-and voltage-dependence of current carried by the CCh - activated ICAN like current in BLA PNs, and highlight its ability to promote a suprathreshold ADP capable of generating sustained firing after a brief excitatory stimulus. Improved understanding of these effectors will provide potentially valuable new insights on the wide range of mechanisms through which cholinergic system dysfunction can lead to impaired executive function.

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bioRxiv2024

An anesthetized rat assay for evaluating the effects of organophosphate-based compounds and countermeasures on intracranial EEG and respiratory rate.

The development of medical countermeasures (MCMs) against organophosphate (OP) induced poisoning is of substantial importance. Use of conventional therapeutics is complicated by off-target effects and restricted penetration of the blood-brain barrier (BBB). Therefore, a concerted effort is underway to discover improved acetylcholinesterase (AChE) reactivators, muscarinic acetylcholine receptor (mAChR) antagonists, and other countermeasures with broader spectrum activity and enhanced CNS efficacy. We recently developed a rat brain slice assay to assess the efficacy of AChE reactivators and mAChR antagonists against the acute effects of the organophosphorus AChE inhibitor 4-nitrophenyl isopropyl methylphosphonate (NIMP) in the basolateral amygdala (BLA). Here we introduce a complimentary anesthetized animal model to evaluate the same compounds in vivo with concurrent monitoring of EEG and respiratory rate. We find that intravenous delivery of 0.5 mg/kg NIMP reliably produces seizure like activity in the BLA, with concurrent respiratory depression and eventual respiratory failure. The central effects of AChE reactivators and mAChR antagonists delivered intravenously are consistent with their expected ability to cross the BBB. Combining our previously described in vitro assay with the methods described here provides a relatively comprehensive set of preclinical tools for evaluating the efficacy of novel MCMs. Notably, using these methods potentially obviates subjecting conscious animals to cholinergic crises, which aligns with the AAALACs 3Rs principle of refinement.

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bioRxiv2023

Circuit and cell-specific contributions to decision making involving risk of explicit punishment in male and female rats.

Decision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit- and cell type-specific optogenetic approaches in rats during a decision-making task involving risk of punishment. In Experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in Experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision-making task, BLA[->]NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA[->]NAcSh during deliberation (the time between trial initiation and choice) increased choice of the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.

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bioRxiv2021

Dendritic membrane resistance modulates activity-induced Ca2+ influx in oxytocinergic magnocellular neurons of mouse PVN

Hypothalamic oxytocinergic magnocellular neurons have a fascinating ability to release peptide from both their axon terminals and from their dendrites. Existing data indicates there is a flexible relationship between somatic activity and dendritic release, but the mechanisms governing this relationship are not completely understood. Here we use a combination of electrical and optical recording techniques to quantify activity-dependent calcium influx in proximal vs. distal dendrites of oxytocinergic magnocellular neurons located in the paraventricular nucleus of the hypothalamus (OT-MCNs). Results reveal that the dendrites of OT-MCNs are weak conductors of somatic voltage changes, and yet activity-induced dendritic calcium influx can be robustly regulated by a diverse set of stimuli that open or close ionophores located along the dendritic membrane. Overall, this study reveals that dendritic membrane resistance is a dynamic and endogenously regulated feature of OT-MCNs that is likely to have substantial functional impact on central oxytocin release. IMPACT STATEMENTActivity-induced dendritic calcium influx in oxytocinergic magnocellular neurons can be robustly modulated by a highly diverse set of stimuli acting on distinct types of ionophores expressed along the dendritic membrane.

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bioRxiv2019

Aging alters the role of basolateral amygdala in intertemporal choice

Aging is associated with an increased ability to delay gratification. Moreover, even when matched for performance, young and aged subjects recruit distinct brain circuitry to complete complex cognitive tasks. Experiments herein used an optogenetic approach to test whether altered recruitment of the basolateral amygdala (BLA), a brain region implicated in valuation of reward-cost contingencies, contributes to age-dependent changes in intertemporal decision making. BLA inactivation while rats deliberated prior to choices between options that yielded either small, immediate or large, delayed rewards rendered both young and aged rats less impulsive. In contrast, BLA inactivation after choices were made (during evaluation of choice outcomes) rendered young rats more impulsive but had no effect in aged rats. These data define multiple, temporally-discrete roles for BLA circuits in intertemporal decision making and implicate altered recruitment of BLA in the elevated preference for delayed rewards that is characteristic of advanced age. Impact StatementBasolateral amygdala (BLA) performs multiple, temporally-discrete functions during intertemporal decision making. Differential engagement of BLA contributes to the enhanced ability to delay gratification that is characteristic of advanced ages.

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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.

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bioRxiv2017

Optogenetic inhibition reveals distinct roles for basolateral amygdala activity at discrete timepoints during risky decision making

Decision making is a multifaceted process, consisting of several distinct phases that likely require different cognitive operations. Previous work showed that the basolateral amygdala (BLA) is a critical substrate for decision making involving risk of punishment; however, it is unclear how the BLA is recruited at different stages of the decision process. To this end, the current study used optogenetics to inhibit the BLA during specific task phases in a model of risky decision making (Risky Decision-making Task; RDT) in which rats choose between a small, \"safe\" reward and a large reward accompanied by varying probabilities of footshock punishment. Rats received intra-BLA microinjections of viral vectors carrying either halorhodopsin (eNpHR3.0-mCherry) or mCherry alone (control) followed by optic fiber implants and were trained in the RDT. Laser stimulation during the task occurred during either intertrial interval, deliberation, or reward outcome phases, the latter of which was further divided into the three possible outcomes (small, safe; large, unpunished; large, punished). Inhibition of the BLA selectively during the deliberation phase decreased choice of the large, risky outcome (decreased risky choice). In contrast, BLA inhibition selectively during delivery of the large, punished outcome increased risky choice. Inhibition had no effect during the other phases, nor did it affect performance in control rats. Collectively, these data indicate that the BLA can either inhibit or promote choice of risky options, depending on the phase of the decision process in which it is active.\n\nSignificance StatementTo date, most behavioral neuroscience research on neural mechanisms of decision making has employed techniques that preclude assessment of distinct phases of the decision process. Here we show that optogenetic inhibition of the basolateral amygdala (BLA) has opposite effects on choice behavior in a rat model of risky decision making depending on the phase in which inhibition occurs. BLA inhibition during a period of deliberation between small, safe and large, risky outcomes decreased risky choice. In contrast, BLA inhibition during receipt of the large, punished outcome increased risky choice. These findings highlight the importance of temporally targeted approaches to understand neural substrates underlying complex cognitive processes. More importantly, they reveal novel information about dynamic BLA modulation of risky choice.

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