Bachelor of Arts, University of Colorado Boulder (2011)
Doctor of Philosophy, University of Texas Austin (2019)
Robert Malenka, Postdoctoral Faculty Sponsor
Modulation of 5-HT release by dynorphin mediates social deficits during opioid withdrawal.
Social isolation during opioid withdrawal is a major contributor to the current opioid addiction crisis. We find that sociability deficits during protracted opioid withdrawal in mice require activation of kappa opioid receptors (KORs) in the nucleus accumbens (NAc) medial shell. Blockade of release from dynorphin (Pdyn)-expressing dorsal raphe neurons (DRPdyn), but not from NAcPdyn neurons, prevents these deficits in prosocial behaviors. Conversely, optogenetic activation of DRPdyn neurons reproduced NAc KOR-dependent decreases in sociability. Deletion of KORs from serotonin (5-HT) neurons, but not from NAc neurons or dopamine (DA) neurons, prevented sociability deficits during withdrawal. Finally, measurements with the genetically encoded GRAB5-HT sensor revealed that during withdrawal KORs block the NAc 5-HT release that normally occurs during social interactions. These results define a neuromodulatory mechanism that is engaged during protracted opioid withdrawal to induce maladaptive deficits in prosocial behaviors, which in humans contribute to relapse.
View details for DOI 10.1016/j.neuron.2022.09.024
View details for PubMedID 36202097
Somatodendritic Release of Cholecystokinin Potentiates GABAergic Synapses Onto Ventral Tegmental Area Dopamine Cells.
BACKGROUND: Neuropeptides are contained in nearly every neuron in the central nervous system and can be released not only from nerve terminals but also from somatodendritic sites. Cholecystokinin (CCK), among the most abundant neuropeptides in the brain, is expressed in the majority of midbrain dopamine neurons. Despite this high expression, CCK function within the ventral tegmental area (VTA) is not well understood.METHODS: We confirmed CCK expression in VTA dopamine neurons through immunohistochemistry and in situ hybridization and detected optogenetically induced CCK release using an enzyme-linked immunosorbent assay. To investigate whether CCK modulates VTA circuit activity, we used whole-cell patch clamp recordings in mouse brain slices. We infused CCK locally invivo and tested food intake and locomotion in fasted mice. We also used invivo fiber photometry to measure Ca2+ transients in dopamine neurons during feeding.RESULTS: Here we report that VTA dopamine neurons release CCK from somatodendritic regions, where it triggers long-term potentiation of GABAergic (gamma-aminobutyric acidergic) synapses. The somatodendritic release occurs during trains of optogenetic stimuli or prolonged but modest depolarization and is dependent on synaptotagmin-7 and T-type Ca2+ channels. Depolarization-induced long-term potentiation is blocked by a CCK2 receptor antagonist and mimicked by exogenous CCK. Local infusion of CCK invivo inhibits food consumption and decreases distance traveled in an open field test. Furthermore, intra-VTA-infused CCK reduced dopamine cell Ca2+ signals during food consumption after an overnight fast and was correlated with reduced food intake.CONCLUSIONS: Our experiments introduce somatodendritic neuropeptide release as a previously unknown feedback regulator of VTA dopamine cell excitability and dopamine-related behaviors.
View details for DOI 10.1016/j.biopsych.2022.06.011
View details for PubMedID 35961792
Friend of the Devil: Negative Social Influences Driving Substance Use Disorders.
Frontiers in behavioral neuroscience
2022; 16: 836996
Substance use disorders in humans have significant social influences, both positive and negative. While prosocial behaviors promote group cooperation and are naturally rewarding, distressing social encounters, such as aggression exhibited by a conspecific, are aversive and can enhance the sensitivity to rewarding substances, promote the acquisition of drug-taking, and reinstate drug-seeking. On the other hand, withdrawal and prolonged abstinence from drugs of abuse can promote social avoidance and suppress social motivation, accentuating drug cravings and facilitating relapse. Understanding how complex social states and experiences modulate drug-seeking behaviors as well as the underlying circuit dynamics, such as those interacting with mesolimbic reward systems, will greatly facilitate progress on understanding triggers of drug use, drug relapse and the chronicity of substance use disorders. Here we discuss some of the common circuit mechanisms underlying social and addictive behaviors that may underlie their antagonistic functions. We also highlight key neurochemicals involved in social influences over addiction that are frequently identified in comorbid psychiatric conditions. Finally, we integrate these data with recent findings on (±)3,4-methylenedioxymethamphetamine (MDMA) that suggest functional segregation and convergence of social and reward circuits that may be relevant to substance use disorder treatment through the competitive nature of these two types of reward. More studies focused on the relationship between social behavior and addictive behavior we hope will spur the development of treatment strategies aimed at breaking vicious addiction cycles.
View details for DOI 10.3389/fnbeh.2022.836996
View details for PubMedID 35221948
Gray areas: Neuropeptide circuits linking the Edinger-Westphal and Dorsal Raphe nuclei in addiction.
The circuitry of addiction comprises several neural networks including the midbrain-an expansive region critically involved in the control of motivated behaviors. Midbrain nuclei like the Edinger-Westphal (EW) and dorsal raphe (DR) contain unique populations of neurons that synthesize many understudied neuroactive molecules and are encircled by the periaqueductal gray (PAG). Despite the proximity of these special neuron classes to the ventral midbrain complex and surrounding PAG, functions of the EW and DR remain substantially underinvestigated by comparison. Spanning approximately -3.0 to -5.2 mm posterior from bregma in the mouse, these various cell groups form a continuum of neurons that we refer to collectively as the subaqueductal paramedian zone. Defining how these pathways modulate affective behavioral states presents a difficult, yet conquerable challenge for today's technological advances in neuroscience. In this review, we cover the known contributions of different neuronal subtypes of the subaqueductal paramedian zone. We catalogue these cell types based on their spatial, molecular, connectivity, and functional properties and integrate this information with the existing data on the EW and DR in addiction. We next discuss evidence that links the EW and DR anatomically and functionally, highlighting the potential contributions of an EW-DR circuit to addiction-related behaviors. Overall, we aim to derive an integrated framework that emphasizes the contributions of EW and DR nuclei to addictive states and describes how these cell groups function in individuals suffering from substance use disorders.
View details for DOI 10.1016/j.neuropharm.2021.108769
View details for PubMedID 34481834
- Love it or Leave it: Differential Modulation of Incentive Motivation by Corticotropin-Releasing Factor Neurons. Biological psychiatry 2021; 89 (12): 1113-1115
Extended Amygdala Neuropeptide Circuitry of Emotional Arousal: Waking Up on the Wrong Side of the Bed Nuclei of Stria Terminalis.
Frontiers in behavioral neuroscience
2021; 15: 613025
Sleep is fundamental to life, and poor sleep quality is linked to the suboptimal function of the neural circuits that process and respond to emotional stimuli. Wakefulness ("arousal") is chiefly regulated by circadian and homeostatic forces, but affective mood states also strongly impact the balance between sleep and wake. Considering the bidirectional relationships between sleep/wake changes and emotional dynamics, we use the term "emotional arousal" as a representative characteristic of the profound overlap between brain pathways that: (1) modulate wakefulness; (2) interpret emotional information; and (3) calibrate motivated behaviors. Interestingly, many emotional arousal circuits communicate using specialized signaling molecules called neuropeptides to broadly modify neural network activities. One major neuropeptide-enriched brain region that is critical for emotional processing and has been recently implicated in sleep regulation is the bed nuclei of stria terminalis (BNST), a core component of the extended amygdala (an anatomical term that also includes the central and medial amygdalae, nucleus accumbens shell, and transition zones betwixt). The BNST encompasses an astonishing diversity of cell types that differ across many features including spatial organization, molecular signature, biological sex and hormonal milieu, synaptic input, axonal output, neurophysiological communication mode, and functional role. Given this tremendous complexity, comprehensive elucidation of the BNST neuropeptide circuit mechanisms underlying emotional arousal presents an ambitious set of challenges. In this review, we describe how rigorous investigation of these unresolved questions may reveal key insights to enhancing psychiatric treatments and global psychological wellbeing.
View details for DOI 10.3389/fnbeh.2021.613025
View details for PubMedID 33633549
Dissecting neural mechanisms of prosocial behaviors.
Current opinion in neurobiology
2020; 68: 9–14
Prosocial behaviors are essential for group cooperation, which enrich life experience and enhance survival. These complex behaviors are governed by intricate interactions between numerous neural circuits functioning in concert. Impairments in prosocial interactions result from disruptions of this coordinated brain activity and are a prominent feature of several pathological conditions including autism spectrum disorder, depression and addiction. Here we highlight recent studies that use advanced techniques to anatomically map, monitor and manipulate neural circuits that influence prosocial behavior. These recent findings provide important clues to unravel the complexities of the neural mechanisms that mediate prosocial interactions and offer insights into new strategies for the treatment of aberrant social behavior.
View details for DOI 10.1016/j.conb.2020.11.006
View details for PubMedID 33278639
- A New Look at the Role of Mesoamygdaloid Dopamine Neurons in Aversive Conditioning. The Journal of neuroscience : the official journal of the Society for Neuroscience 2020; 40 (40): 7590–92
Differential regulation of alcohol consumption and reward by the transcriptional cofactor LMO4.
Repeated alcohol exposure leads to changes in gene expression that are thought to underlie the transition from moderate to excessive drinking. However, the mechanisms by which these changes are integrated into a maladaptive response that leads to alcohol dependence are not well understood. One mechanism could involve the recruitment of transcriptional co-regulators that bind and modulate the activity of transcription factors. Our results indicate that the transcriptional regulator LMO4 is one such candidate regulator. Lmo4-deficient mice (Lmo4gt/+) consumed significantly more and showed enhanced preference for alcohol in a 24 h intermittent access drinking procedure. shRNA-mediated knockdown of Lmo4 in the nucleus accumbens enhanced alcohol consumption, whereas knockdown in the basolateral amygdala (BLA) decreased alcohol consumption and reduced conditioned place preference for alcohol. To ascertain the molecular mechanisms that underlie these contrasting phenotypes, we carried out unbiased transcriptome profiling of these two brain regions in wild type and Lmo4gt/+ mice. Our results revealed that the transcriptional targets of LMO4 are vastly different between the two brain regions, which may explain the divergent phenotypes observed upon Lmo4 knockdown. Bioinformatic analyses revealed that Oprk1 and genes related to the extracellular matrix (ECM) are important transcriptional targets of LMO4 in the BLA. Chromatin immunoprecipitation revealed that LMO4 bound Oprk1 promoter elements. Consistent with these results, disruption of the ECM or infusion of norbinaltorphimine, a selective kappa opioid receptor antagonist, in the BLA reduced alcohol consumption. Hence our results indicate that an LMO4-regulated transcriptional network regulates alcohol consumption in the BLA.
View details for DOI 10.1038/s41380-020-0706-8
View details for PubMedID 32144357
Dissecting the Roles of GABA and Neuropeptides from Rat Central Amygdala CRF Neurons in Anxiety and Fear Learning.
2019; 29 (1): 13
Central amygdala (CeA) neurons that produce corticotropin-releasing factor (CRF) regulate anxiety and fear learning. These CeACRF neurons release GABA and several neuropeptides predicted to play important yet opposing roles in these behaviors. We dissected the relative roles of GABA, CRF, dynorphin, and neurotensin in CeACRF neurons in anxiety and fear learning by disrupting their expression using RNAi in male rats. GABA, but not CRF, dynorphin, or neurotensin, regulates baseline anxiety-like behavior. In contrast, chemogenetic stimulation of CeACRF neurons evokes anxiety-like behavior dependent on CRF and dynorphin, but not neurotensin. Finally, knockdown of CRFand dynorphin impairs fear learning, whereas knockdown of neurotensin enhances it. Our results demonstrate distinct behavioral roles for GABA, CRF, dynorphin, and neurotensin in a subpopulation of CeA neurons. These results highlight the importance of considering the repertoire of signaling molecules released from a given neuronal population when studying the circuit basis of behavior.
View details for DOI 10.1016/j.celrep.2019.08.083
View details for PubMedID 31577943
Promoting activity of (α4)3(β2)2 nicotinic cholinergic receptors reduces ethanol consumption.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
There is increasing interest in developing drugs that act at α4β2 nicotinic acetylcholine receptors (nAChRs) to treat alcohol use disorder. The smoking cessation agent varenicline, a partial agonist of α4β2 nAChRs, reduces alcohol intake, but its use can be limited by side effects at high therapeutic doses. There are two stoichiometric forms of α4β2 nAChRs, (α4)3(β2)2 and (α4)2(β2)3. Here we investigated the hypothesis that NS9283, a positive allosteric modulator selective for the (α4)3(β2)2 form, reduces ethanol consumption. NS9283 increased the potency of varenicline to activate and desensitize (α4)3(β2)2 nAChRs in vitro without affecting other known targets of varenicline. In male and female C57BL/6J mice, NS9283 (10 mg/kg) reduced ethanol intake in a two-bottle choice, intermittent drinking procedure without affecting saccharin intake, ethanol-induced incoordination or ethanol-induced loss of the righting reflex. Subthreshold doses of NS9283 (2.5 mg/kg) plus varenicline (0.1 mg/kg) synergistically reduced ethanol intake in both sexes. Finally, despite having no aversive valence of its own, NS9283 enhanced ethanol-conditioned place aversion. We conclude that compounds targeting the (α4)3(β2)2 subtype of nAChRs can reduce alcohol consumption, and when administered in combination with varenicline, may allow use of lower varenicline doses to decrease varenicline side effects.
View details for DOI 10.1038/s41386-019-0475-8
View details for PubMedID 31394567
Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats.
2019; 10 (1): 1238
The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRFCeA-BNST pathway is mediated by inhibition of the CRF-CRF1 system and inhibition of BNST cell firing. These results suggest that the CRFCeA-BNST pathway could be targeted for the treatment of excessive drinking in alcohol use disorder.
View details for DOI 10.1038/s41467-019-09183-0
View details for PubMedID 30886240
View details for PubMedCentralID PMC6423296
A Corticotropin Releasing Factor Network in the Extended Amygdala for Anxiety.
The Journal of neuroscience : the official journal of the Society for Neuroscience
2019; 39 (6): 1030-1043
The central amygdala (CeA) is important for fear responses to discrete cues. Recent findings indicate that the CeA also contributes to states of sustained apprehension that characterize anxiety, although little is known about the neural circuitry involved. The stress neuropeptide corticotropin releasing factor (CRF) is anxiogenic and is produced by subpopulations of neurons in the lateral CeA and the dorsolateral bed nucleus of the stria terminalis (dlBST). Here we investigated the function of these CRF neurons in stress-induced anxiety using chemogenetics in male rats that express Cre recombinase from a Crh promoter. Anxiety-like behavior was mediated by CRF projections from the CeA to the dlBST and depended on activation of CRF1 receptors and CRF neurons within the dlBST. Our findings identify a CRFCeA→CRFdlBST circuit for generating anxiety-like behavior and provide mechanistic support for recent human and primate data suggesting that the CeA and BST act together to generate states of anxiety.SIGNIFICANCE STATEMENT Anxiety is a negative emotional state critical to survival, but persistent, exaggerated apprehension causes substantial morbidity. Identifying brain regions and neurotransmitter systems that drive anxiety can help in developing effective treatment. Much evidence in rodents indicates that neurons in the bed nucleus of the stria terminalis (BST) generate anxiety-like behaviors, but more recent findings also implicate neurons of the CeA. The neuronal subpopulations and circuitry that generate anxiety are currently subjects of intense investigation. Here we show that CeA neurons that release the stress neuropeptide corticotropin-releasing factor (CRF) drive anxiety-like behaviors in rats via a pathway to dorsal BST that activates local BST CRF neurons. Thus, our findings identify a CeA→BST CRF neuropeptide circuit that generates anxiety-like behavior.
View details for DOI 10.1523/JNEUROSCI.2143-18.2018
View details for PubMedID 30530860
View details for PubMedCentralID PMC6363927
Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice.
2018; 84 (3): 193-201
Despite the high cost and widespread prevalence of alcohol use disorders, treatment options are limited, underscoring the need for new, effective medications. Previous results using protein kinase C epsilon (PKCε) knockout mice, RNA interference against PKCε, and peptide inhibitors of PKCε predict that small-molecule inhibitors of PKCε should reduce alcohol consumption in humans.We designed a new class of PKCε inhibitors based on the Rho-associated protein kinase (ROCK) inhibitor Y-27632. In vitro kinase and binding assays were used to identify the most potent compounds. Their effects on ethanol-stimulated synaptic transmission; ethanol, sucrose, and quinine consumption; ethanol-induced loss of righting; and ethanol clearance were studied in mice.We identified two compounds that inhibited PKCε with Ki <20 nM, showed selectivity for PKCε over other kinases, crossed the blood-brain barrier, achieved effective concentrations in mouse brain, prevented ethanol-stimulated gamma-aminobutyric acid release in the central amygdala, and reduced ethanol consumption when administered intraperitoneally at 40 mg/kg in wild-type but not in Prkce-/- mice. One compound also reduced sucrose and saccharin consumption, while the other was selective for ethanol. Both transiently impaired locomotion through an off-target effect that did not interfere with their ability to reduce ethanol intake. One compound prolonged recovery from ethanol-induced loss of righting but this was also due to an off-target effect since it was present in Prkce-/- mice. Neither altered ethanol clearance.These results identify lead compounds for development of PKCε inhibitors that reduce alcohol consumption.
View details for DOI 10.1016/j.biopsych.2017.10.017
View details for PubMedID 29198469
View details for PubMedCentralID PMC5984071
Cooperative CRF and α1 Adrenergic Signaling in the VTA Promotes NMDA Plasticity and Drives Social Stress Enhancement of Cocaine Conditioning.
2018; 22 (10): 2756-2766
Stressful events rapidly trigger activity-dependent synaptic plasticity, driving the formation of aversive memories. However, it remains unclear how stressful experience affects plasticity mechanisms to regulate appetitive learning, such as intake of addictive drugs. Using rats, we show that corticotropin-releasing factor (CRF) and α1 adrenergic receptor (α1AR) signaling enhance the plasticity of NMDA-receptor-mediated glutamatergic transmission in ventral tegmental area (VTA) dopamine (DA) neurons through distinct effects on inositol 1,4,5-triphosphate (IP3)-dependent Ca2+ signaling. We find that CRF amplifies IP3-Ca2+ signaling induced by stimulation of α1ARs, revealing a cooperative mechanism that promotes glutamatergic plasticity. In line with this, acute social defeat stress engages similar cooperative CRF and α1AR signaling in the VTA to enhance learning of cocaine-paired cues. These data provide evidence that CRF and α1ARs act in concert to regulate IP3-Ca2+ signaling in the VTA and promote learning of drug-associated cues.
View details for DOI 10.1016/j.celrep.2018.02.039
View details for PubMedID 29514102
View details for PubMedCentralID PMC5877815
The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target?
Alcoholism, clinical and experimental research
2017; 41 (12): 1986-1999
Corticotropin releasing factor (CRF) is a neuropeptide that plays a key role in behavioral and physiological responses to stress. A large body of animal literature implicates CRF acting at type 1 CRF receptors (CRFR1) in consumption by alcohol-dependent subjects, stress-induced reinstatement of alcohol seeking, and possibly binge alcohol consumption. These studies have encouraged recent pilot studies of CRFR1 antagonists in humans with alcohol use disorder (AUD). It was a great disappointment to many in the field that these studies failed to show an effect of these compounds on stress-induced alcohol craving. Here, we examine these studies to explore potential limitations and discuss preclinical and human literature to ask whether CRFR1 is still a valid drug target to pursue for the treatment of AUD.
View details for DOI 10.1111/acer.13507
View details for PubMedID 28940382
View details for PubMedCentralID PMC5711524
Repeated social defeat stress enhances glutamatergic synaptic plasticity in the VTA and cocaine place conditioning.
Enduring memories of sensory cues associated with drug intake drive addiction. It is well known that stressful experiences increase addiction vulnerability. However, it is not clear how repeated stress promotes learning of cue-drug associations, as repeated stress generally impairs learning and memory processes unrelated to stressful experiences. Here, we show that repeated social defeat stress in rats causes persistent enhancement of long-term potentiation (LTP) of NMDA receptor-mediated glutamatergic transmission in the ventral tegmental area (VTA). Protein kinase A-dependent increase in the potency of inositol 1,4,5-triphosphate-induced Ca(2+) signaling underlies LTP facilitation. Notably, defeated rats display enhanced learning of contextual cues paired with cocaine experience assessed using a conditioned place preference (CPP) paradigm. Enhancement of LTP in the VTA and cocaine CPP in behaving rats both require glucocorticoid receptor activation during defeat episodes. These findings suggest that enhanced glutamatergic plasticity in the VTA may contribute, at least partially, to increased addiction vulnerability following repeated stressful experiences.
View details for DOI 10.7554/eLife.15448
View details for PubMedID 27374604
View details for PubMedCentralID PMC4931908
DAT isn't all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling.
2015; 20 (12): 1525-37
The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine's ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-like receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment.
View details for DOI 10.1038/mp.2014.177
View details for PubMedID 25644383
View details for PubMedCentralID PMC4523496