Biology subjects

Hart, E. E.

Publications and source records attributed to Hart, E. E..

4 recordsLinked to original sources

bioRxiv2025

Generation and characterization of a tamoxifen-inducible, Cre driver rat for transgene expression in microglia

Microglia are the resident immune cells of the central nervous system (CNS) and display diverse functions under both physiological and pathological conditions. The past decade has seen burgeoning interest in microglia function, with a variety of transgenic tools developed for specific genetic manipulation of microglia in various injury, disease, and developmental models. Although the majority of models have been developed in mice, the ability to manipulate microglia in rats provides additional advantages to studying microglial function in the brain especially related to complex behavior. Using BAC transgenesis, our lab has created a transgenic rat (Cx3cr1-CreERT2) that expresses a tamoxifen inducible Cre recombinase (CreERT2) under control of the microglial/macrophage specific fractalkine C-X3-C Motif Chemokine Receptor 1 (Cx3cr1) promoter. In mice, CreERT2 and other transgenes have been expressed in microglia using the Cx3cr1 promoter, however, this is the first demonstration in rats. Importantly, these rats exhibit similar cognitive behaviors compared to their wildtype (WT) controls. Microglial specificity of inducible Cre expression was confirmed by breeding the novel Cx3cr1-CreERT2+/- rat with a previously reported double floxed inverse open reading frame (DIO)-mCherry+/- reporter rat to show tamoxifen inducible mCherry expression that colocalizes with the microglial marker Iba1. In addition, we utilize flow cytometry to demonstrate time and Cre dependent differences in recombination of Cx3cr1+ cells in the spleen, peripheral blood, and brain at two- and eight-weeks post-tamoxifen treatment. Overall, we have created a novel transgenic rat model for researchers to employ in understanding microglial and peripheral immune cell function in rats.

neuroscience↗

bioRxiv2019

Anterior cingulate cortex activity regulates effort-based decision making

The anterior cingulate cortex (ACC) is implicated in effort exertion and choices based on effort cost, but it is still unclear how it mediates this cost-benefit evaluation. Here, male rats were trained to exert effort for a high-value reward (sucrose pellets) in a progressive ratio lever pressing task. Trained rats were then tested in two conditions: a no-choice condition where lever pressing for sucrose was the only available food option, and a choice condition where a low-value reward (lab chow) was freely available as an alternative to pressing for sucrose. Disruption of ACC--via either chemogenetic inhibition or excitation--reduced lever pressing in the choice, but not in the no-choice, condition. We next looked for value coding cells in ACC during effortful behavior and reward consumption phases during choice and no-choice conditions. For this, we utilized in vivo miniaturized fluorescence microscopy to reliably track responses of the same cells and compare how ACC neurons respond during the same effortful behavior where there was a choice versus when there was no-choice. We found that lever-press and sucrose-evoked responses were significantly weaker during choice compared to no-choice sessions, which may have rendered them more susceptible to chemogenetic disruption. Taken together, findings from our interference experiments and neural recordings suggest that a mechanism by which ACC mediates effortful decisions is in the discrimination of the utility of available options. ACC regulates these choices by providing a stable population code for the relative value of different options. Significance StatementThe anterior cingulate cortex (ACC) is implicated in effort-based decision making. Here, we used chemogenetics and in vivo calcium imaging to explore its mechanism. Rats were trained to lever press for a high-value reward and tested in two conditions: a no-choice condition where lever pressing for the high-value reward was the only option, and a choice condition where a low-value reward was also available. Inhibition or excitation of ACC reduced effort toward the high value option, but only in the choice condition. Neural responses in ACC were weaker in the choice compared to the no-choice condition. A mechanism by which ACC regulates effortful decisions is in providing a stable population code for the discrimination of the utility of available options.

neuroscience↗

bioRxiv2019

Dissociable roles for Anterior Cingulate Cortex and Basolateral Amygdala in Decision Confidence and Learning under Uncertainty

It has been suggested the subjective sense of certainty, or confidence, in ambiguous sensory cues can alter the interpretation of reward feedback and facilitate learning. We trained rats to report the orientation of ambiguous visual stimuli according to a spatial stimulus-response rule. Following choice, rats could wait a self-timed delay for reward or initiate a new trial. Waiting times increased with discrimination accuracy, demonstrating that this measure could be used as a proxy for confidence. Chemogenetic silencing of BLA shortened waiting times overall whereas ACC inhibition rendered waiting times insensitive to confidence-modulating attributes of visual stimuli, suggesting contribution of ACC but not BLA to confidence computations. Subsequent reversal learning was enhanced by confidence. Both ACC and BLA inhibition blocked this enhancement but via differential modulation of learning strategies and consistency in using learned rules. Altogether, we demonstrate dissociable roles for ACC and BLA in transmitting confidence and learning under uncertainty.

neuroscience↗

bioRxiv2019

Individual vulnerability to stress is associated with increased demand for intravenous heroin self-administration in rats

Opioid use is a widespread epidemic, and traumatic stress exposure is a critical risk factor in opioid use and relapse. There is a significant gap in our understanding of how stress contributes to heroin use, and there are limited studies investigating individual differences underlying stress reactivity and subsequent stress-induced heroin self-administration. We hypothesized that greater individual vulnerability to stress would predict higher demand for heroin self-administration in a within-subjects rodent model of stress and heroin use comorbidity. Male rats were exposed to inescapable intermittent swim stress and individual biological (corticosterone) or behavioral (open field, social exploration, and forced swim tests) measures were assessed before and after the stress episode. Individual demand for self-administered heroin (0.05 mg/kg/infusion; 12-hour sessions) was assessed using a behavioral economics approach followed by extinction and reinstatement tests triggered by stress re-exposure, non-contingent cue presentations, and yohimbine (0, 1.0, or 2.5 mg/kg). We found that behavioral, biological, and a combination of behavioral and biological markers sampled prior and after the stress episode that occurred weeks before the access to heroin selfadministration predicted the magnitude of individual demand for heroin. Non-contingent presentation of cues, that were previously associated with heroin, reinstated heroin seeking in extinction. For the first time, we show that individual biological response to an ecologically relevant stressor in combination with associated behavioral markers can be used to predict subsequent economic demand for heroin.

neuroscience↗