124 research outputs found
NEURAL DYNAMICS OF COGNITIVE FLEXIBILITY: META-RPE SIGNALING WITHIN A PRELIMBIC CORTEX-VENTRAL TEGMENTAL AREA CIRCUIT EXPEDITES CONTINGENCY DEGRADATION DURING COGNITIVE FLEXIBILITY
No full textThesis (Ph.D.)--University of Washington, 2024Although tightly associated with prefrontal cortex (PFC), concrete cognitive flexibility signals have historically been ill defined. One common test of cognitive flexibility involves reversal learning, where the contingencies of discrete learned cues are enhanced or degraded, and an individual subsequently must flexibly remap their behavior. This work presents meta-RPE (mRPE), a cognitive flexibility signal that peaks in the middle of reversal behavior and represents the average of repeated, concentrated errors over many trials. Allowing mRPE to modulate canonical single-trial reward prediction errors (RPEs) expedites reversal learning and fits observed animal behavior better than models with static learning rates. Using novel statistical and imaging methods, this work identifies a subpopulation of neurons in prelimbic cortex (PL), a PFC subregion, that selectively encode a contingency degradation-related mRPE signal and can directly modify RPE via preferential representation in projections to VTA. Otherwise stable PL dynamics across reversal suggest the mRPE signal is unlikely attributable to representational drift. Dopaminergic innervation to PL does not predict the mRPE signal, instead representing a contingency elevation mRPE signal from elsewhere in the brain. Deriving mRPE and identifying its neural correlate in the PL-VTA circuit represents a quantitative advance in the field’s understanding of cognitive flexibility signaling within the prefrontal cortex
Molecularly-defined cell types within the septal complex and their role in opioid dependence and withdrawal
No full textThesis (Ph.D.)--University of Washington, 2023Opioid withdrawal is an unpleasant experience and produces changes in pain, anxiety, depression, and general dysphoria. Because withdrawal is so intense, persons with opioid use disorder (OUD) often return to drug use to relieve this aversive state. Therefore, it is imperative to understand the neural substrates that are disrupted by opioid dependence and withdrawal. Repeated opioid exposure dysregulates neural circuitry involved in natural reward and aversion, thereby shaping a system that drives drug-seeking. Among limbic brain circuitry, the lateral septum (LS) is a forebrain area that gates motivated behaviors based on environmental and emotional contexts. While in vivo pharmacological studies have linked the LS to drug intake, withdrawal, and reinstatement of drug-seeking behavior, this molecularly heterogeneous region lacks clarity regarding the specific cell-types that are affected by long-term opioid exposure and consequently contribute to maladaptive behaviors during opioid withdrawal. To this end, we used single-nucleus RNA-sequencing (snRNAseq) to develop a transcriptional atlas of LS cell types perturbed during morphine dependence and withdrawal. We discovered that chronic morphine altered the transcriptional landscape of most LS neuronal cell classes, modulating genes involved in synaptic transmission and protein synthesis. Naloxone-precipitated withdrawal had the largest effect on two major cell types, one of which is a group of neurons expressing the gene for Neurotensin (Nts; LS-Nts neurons). Using 2-photon calcium imaging, we demonstrate that LS-Nts neurons in morphine-dependent mice remain more active during prolonged opioid withdrawal. Ex vivo electrophysiology revealed that enhanced glutamatergic drive onto LS-Nts neurons may underlie their hyperactivity in the absence of opioids. Finally, we showed that silencing these neurons via Cre-dependent expression of tetanus toxin light chain (TetTox) during opioid withdrawal exacerbates pain coping behaviors and alters sociability in a sexually-dimorphic manner. Together, these results suggest that LS-Nts neurons are a key neural substrate disrupted during opioid withdrawal and establish the LS as a crucial regulator of adaptive behaviors, specifically pertaining to OUD
Cortical Operation of the Ventral Striatal Switchboard
No full textHow does the ventral striatum (VS) prioritize and process afferent input? In this issue, Calhoon and O’Donnell (2013) demonstrate that cortical projections to the VS can attenuate hippocampal and thalamic VS input, suggesting that the cortex can uniquely control VS circuit dynamics
Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning.
No full textNatural rewards and drugs of abuse can alter dopamine signaling, and ventral tegmental area (VTA) dopaminergic neurons are known to fire action potentials tonically or phasically under different behavioral conditions. However, without technology to control specific neurons with appropriate temporal precision in freely behaving mammals, the causal role of these action potential patterns in driving behavioral changes has been unclear. We used optogenetic tools to selectively stimulate VTA dopaminergic neuron action potential firing in freely behaving mammals. We found that phasic activation of these neurons was sufficient to drive behavioral conditioning and elicited dopamine transients with magnitudes not achieved by longer, lower-frequency spiking. These results demonstrate that phasic dopaminergic activity is sufficient to mediate mammalian behavioral conditioning
Neural dynamic adaptation of extended amygdala to stress and anxiety
No full textAnxiety disorders constitute changes across behavioral, physiological, and psychological dimensions that are driven by expanse neural circuits. However, the bed nucleus of the stria terminalis (BNST), a component of the extended amygdala, plays a crucial role in regulating many aspects of these changes. For instance, activation of specific cells within BNST can drive freezing behavior and while others control physiological arousal. Still, many studies using rodent models have focused on only a handful of behavioral changes. Much of our understanding of the processes related to anxiety, consequently, have been largely based on a few phenotypes, such as avoidance of open and well-lit spaces. Here, I highlight experiments we performed to broaden our understanding of anxiety-related phenotypes and the specific BNST cell types involved. In the first aim, we measure changes in pupil size in the mouse as a proxy for arousal and find that prepronociceptin (Pnoc)-expressing neurons within BNST encode and drive these physiological changes. Further, calcium imaging indicates the cellular responses of these cells to both anxiogenic stimuli and changes in arousal are varied. This underlying heterogeneity may be the means for a broad role for BNST in controlling aspects of anxiety-related processes. For the second aim, we investigate how anxiety-like states can induce changes in behavior using more quantitative, computational analysis. We administer the alpha 2-adrenergic antagonist yohimbine to induce anxiety-like states in mice and find that these states produces a wealth of changes in behavioral expression. Further using traditional behavioral analysis would have failed to appreciate these alterations. Together, these studies highlight the advantages of taking a diverse approach to understanding anxiety-related phenotypes. The information we gain will likely accelerate our understanding of anxiety disorders and ultimately drive us toward better treatment for the disease.Doctor of Philosoph
Dissecting the Role of Amygdala Circuits in the Control of Fear Extinction and Alcohol Drinking
No full textSubstance use disorders and mood disorders exhibit high co-morbidity suggesting that these conditions may result from changes in common neurocircuits. Here we examine how outputs to and from the amygdala are altered in models of excessive alcohol use and Post-Traumatic Stress Disorder (PTSD). In the first set of experiments, we used extinction of Pavlovian conditioned fear to understand the type of learning that is impaired in patients with PTSD. Using retrograde anatomical tract tracing, we found that distinct sets of neurons in the Prefrontal Cortex (PFC) project to the Basolateral Amygdala (BLA) and Nucleus Accumbens (NAc). Next, we demonstrated that fear extinction results in output-specific changes in excitability wherein PFC projections to the BLA showed increased excitability after extinction training whereas the excitability of NAc outputs were unaltered. Finally, we found that the PFC to BLA pathway is required for extinction recall in vivo as pathway-specific chemogenetic inhibition impaired the recall of a previously acquired extinction memory. These experiments refine our understanding of the role of PFC in mediating fear extinction, and suggest that projections to the amygdala may be a potential therapeutic target in treating PTSD. In the second set of experiments, we examine the contribution of the endogenous opioid system in the Central Amygdala (CeA) to regulating excessive alcohol drinking. We find that the Kappa Opioid Receptor (KOR) is expressed on largely separate sets of neurons in the CeA than its endogenous ligand Dynorphin (PDYN). Knockout of KOR results in reductions in alcohol drinking in male, but not female animals whereas knockout of PDYN results in reduced alcohol intake in both sexes. These changes were observed without alterations in consummatory or anxiety-like behavior. There were also sex-specific alterations in CeA physiology as chronic alcohol decreased the excitability decreased the excitability of PDYN neurons in female, but not male animals. These findings highlight the potential utility of KOR antagonists in treating Alcohol Use Disorders and demonstrate the need to systematically investigate sex differences in the endogenous opioid system. Taken together these experiments support using genetic and anatomical specificity to understand the role of brain region and cell type in this behavior. These approaches will ultimately lead to a more thorough understanding of the alterations in neural circuits that underlie psychiatric conditions.Doctor of Philosoph
Transcriptional Representations in Discrete Neural Systems and Their Tuning by Chronic Physiological Pressures
No full textThe emergence of complex behavioral, sensory, and cognitive capacities in bilaterian animals was enabled by the evolution of diverse ensembles of neuronal cell-types. To understand how discrete populations of neurons participate in complex circuit-level processes, contemporary systems-level approaches have sought to assign cell-type-specific transcriptional features to define heterogeneous populations across the brain. However, gene expression is inherently plastic, and how discrete neuronal cell-types are sculpted by systemic pressures is not well understood. Here, we leverage high-throughput single-cell RNA-sequencing to explore how chronic pressures are represented across discrete neural systems in brain regions that are involved in the homeostatic responses to these pressures. We study this concept of transcriptional allostasis through two different models. First, we examine how lateral hypothalamic area neurons are shaped by chronic high fat diet in obesity. Next, we investigate the kinetics of cell-type-specific alterations in transcriptional states within the nucleus accumbens and medial thalamic complex during spontaneous withdrawal from escalating morphine. With this, we identify and characterize discrete substrates that are uniquely sensitive to biologically-relevant allostatic pressures, thereby potentially contributing to the development of associated maladaptive states in these systems.Doctor of Philosoph
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