References and Links to Papers
STRIATAL LOW-THRESHOLD SPIKING INTERNEURONS LOCALLY GATE DOPAMINE
Current Biology (in press)
Holly EN^, Davatolhagh MF, España RA, Fuccillo MV^
Dopamine is critically involved in a wide range of behaviors, but recent evidence points to a clear divergence of dopamine cell body activity and local dopamine concentrations. Here, we show a novel mechanism by which low-threshold spiking interneurons (LTSIs) in the dorsomedial striatum (DMS) can locally gate striatal dopamine, and that these LTSI-dopamine interactions play a key role in goal-directed learning.
STRIATAL LOW-THRESHOLD SPIKING INTERNEURONS REGULATE GOAL-DIRECTED LEARNING
Holly EN, Davatolhagh MF, Choi K, Alabi OO, Vargas Cifuentes L, Fuccillo MV.
The dorsomedial striatum (DMS) plays a key role in goal-directed behaviors. The DMS is comprised primarily of spiny projection neurons (SPNs), which are under local regulation by small classes of interneurons. The functional role of one striatal interneuron subtype, low-threshold spiking interneurons (LTSIs) during behavior was largely unexplored. Here, using calcium imaging, optogenetic, and intersectional genetics approaches, we discovered that these LTSI cells exhibit reward-circumscribed activity that decreases with and causally modulates goal-directed learning.
INTEGRATED ANATOMICAL AND PHYSIOLOGICAL MAPPING OF STRIATAL AFFERENT PROJECTIONS
European Journal of Neuroscience (2019)
Choi, K*, Holly EN*, Davatolhagh MF, Beier KT, Fuccillo MV
The dorsomedial striatum, a key site of reward-sensitive motor output, receives extensive afferent input from cortex, thalamus and midbrain. These projections are integrated by striatal microcircuits containing both spiny projection neurons (SPNs) and local circuit interneurons. Using cell-type specific tracing, we described the whole-brain inputs to SPNs and two classes of interneurons, low-threshold spiking (LTSI) and fast spiking (FSI) interneurons. Using slice electrophysiology and novel quantitative optogenetic measures to probe synaptic strength, we found significant divergence between cell type-specific anatomical connectivity and measures of excitatory synaptic strength, particularly for LTSIs.
EPISODIC SOCIAL STRESS-ESCALATED COCAINE SELF-ADMINISTRATION: ROLE OF PHASIC AND TONIC CORTICOTROPIN RELEASING FACTOR IN THE ANTERIOR AND POSTERIOR VENTRAL TEGMENTAL AREA
Journal of Neuroscience (2016)
Holly EN^, Boyson CO, Montagud-Romero S, Gobrogge KL, DeBold JF, Miczek KA
A history of social defeat stress results in later increased cocaine taking and seeking in male rats. Here, we investigated the underlying neural mechanism driving later escalated drug use. Using in vivo microdialysis, we discovered that the stress-related peptide corticotropin releasing factor (CRF) is released in the ventral tegmental area (VTA), the home of dopamine cell bodies that is fundamentally involved in reward. Using pharmacology, we showed that CRF signaling in the VTA both during and after stress is a key driver of escalated cocaine taking and seeking behavior.
VENTRAL TEGMENTAL AREA DOPAMINE REVISITED: EFFECTS OF ACUTE AND REPEATED STRESS
Holly EN^, Miczek KA
The ventral tegmental area (VTA) is the source of mesocorticolimbic dopamine. VTA dopamine has canonically been associated with reward and reward prediction error, but here we review a rapidly growing literature demonstrating VTA dopamine is also potently released during both acute and repeated stress.
CAPTURING INDIVIDUAL DIFFERENCES: CHALLENGES IN ANIMAL MODELS OF POSTTRAUMATIC STRESS DISORDER AND DRUG ABUSE
Biological Psychiatry (2015)
Holly EN^, Miczek KA
Many psychiatric disorders are comorbid with substance use disorders, yet many preclinical studies have struggled to replicate comorbidities in rodents, particularly in models for psychiatric disorders with anhedonia. In this commentary, we highlight the importance of both time course and individual differences when studying stress-related disorders, emphasizing that individual differences are a desirable goal, not a limitation in preclinical research.
MALADAPTIVE CHOICES BY DEFEATED RATS: LINK BETWEEN RAPID APPROACH TO SOCIAL THREAT AND ESCALATED COCAINE SELF-ADMINISTRATION
Boyson CO*, Holly EN*, Burke AR, Montagud-Romero S, DeBold JF, Miczek KA
Social defeat stress causes persistent neuroadaptations that can result in later increased cocaine taking and seeking. However, there are individual differences in stress-escalated cocaine self-administration behavior, which may be a direct result of individual differences in the manner in which rats experience social defeat stress. Here, we dissected the discrete behavioral phases of social defeat stress in rats and analyzed which behavioral characteristics may be predictive of subsequent cocaine self-administration. We discovered that the latency to enter a threatening environment is a novel behavioral characteristic predictive of later cocaine self-administration.
INCREASED MESOCORTICOLIMBIC DOPAMINE DURING ACUTE AND REPEATED SOCIAL DEFEAT STRESS: MODULATION BY CORTICOTROPIN RELEASING FACTOR RECEPTORS IN THE VENTRAL TEGMENTAL AREA
Holly EN^, DeBold JF, Miczek KA
Stress activates a subset of dopamine neurons in the ventral tegmental area (VTA), increasing extracellular dopamine in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAcSh). The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1 and CRF-R2) are located within the VTA and directly and indirectly influence dopaminergic activity. Here, using pharmacological manipulations and in vivo microdialysis during social defeat stress, we showed that VTA CRF receptor activation is necessary for acute and repeated stress-induced dopamine efflux.
SOCIAL STRESS AND CRF-DOPAMINE INTERACTIONS IN THE VTA: ROLE IN LONG-TERM ESCALATION OF COCAINE SELF-ADMINISTRATION
Journal of Neuroscience (2014)
Boyson CO, Holly EN, Shimamoto A, Albrechet-Souza L, Weiner LA, DeBold JF, Miczek KA
Stress activates many cascades of neural responses, one of which is release of corticotropin releasing factor (CRF) in the hypothalamus as well as extrahypothalamic regions. As intermittent social defeat stress escalates cocaine self-administration behavior, which is driven in large part by dopaminergic neurons in the ventral tegmental area (VTA), we asked whether CRF signaling in the VTA might be driving long-term escalation in drug taking. Our data suggests that interactions between CRF and VTA dopamine neurons are essential for enhanced neural and behavioral responses to cocaine.
GROUP I AND GROUP II METABOTROPIC GLUTAMATE RECEPTORS: ROLE IN PATHOPHYSIOLOGY AND TREATMENT OF MAJOR DEPRESSIVE DISORDER
In Olive, MF (Ed.) Metabotropic Glutamate Receptors: Molecular Mechanisms, Role in Neurological Disorders, and Pharmacological Effects. (2014)
Holly EN, LaCrosse AL, Hillhouse TM
Major depressive disorder is a debilitating chronic, recurring illness. For the past 50 years, drugs that increase the synaptic availability of monoamines (norepinephrine, serotonin, and dopamine) have been used to treat depression, yet these traditional antidepressants have substantial limitations and are not always effective. Recently, the role of the glutamatergic system in the pathophysiology and treatment of MDD has received increased attention. Here, we review Group I and Group II metabotropic glutamate receptors, their role in the pathophysiology of depression, and new potential avenues for treatment
SEX DIFFERENCES IN BEHAVIORAL AND NEURAL CROSS-SENSITIZATION AND ESCALATED COCAINE TAKING AS A RESULT OF SOCIAL DEFEAT STRESS IN RATS
Holly EN^, Shimamoto A, DeBold JF, Miczek KA
Stress history is a major risk factor for the later development of cocaine addiction in humans. Likewise, male rats with a history of intermittent social defeat stress exhibit augmented behavioral and neural responses to cocaine, self-administering cocaine for significantly longer than non-stressed controls in “binge”-like patterns. However, clinical data shows that females are more vulnerable than males at every phase of addiction, and while these sex differences have been shown in rats as well, the impact of social stress in females has been understudied. Here, we show that socially stressed females exhibit larger and longer lasting behavioral and neural cross-sensitization to cocaine, as well as more dysregulated cocaine taking than socially stressed males.
SOCIAL STRESS-ESCALATED INTERMITTENT ALCOHOL DRINKING: MODULATION BY CRF-R1 IN THE VENTRAL TEGMENTAL AREA AND ACCUMBAL DOPAMINE IN MICE
Hwa LS, Holly EN, DeBold JF, Miczek KA
Stress increases alcohol (EtOH) consumption in humans, and here we show that a history of social defeat stress also escalates voluntary EtOH drinking in mice. We further explored a mechanistic link between stress and drinking, finding corticotropin-releasing factor type-1 receptors (CRF-R1) in the dopamine-rich ventral tegmental area (VTA) to be especially important for stress-escalated EtOH drinking. CRF-R1 may be a mechanism for balancing the dysregulation of stress and reward in alcohol use disorders.
AGGRESSION, GLUTAMATE IN THE MPFC, AND WITHDRAWAL FROM INTERMITTENT ALCOHOL IN OUTBRED MICE
Hwa LS, Nathanson AJ, Shimamoto A, Tayeh JK, Wilens AR, Holly EN, Newman EL, DeBold JF, Miczek KA
Disrupted social behavior, including occasional aggressive outbursts, is characteristic of withdrawal from long-term alcohol (EtOH) use. Here, we explore aggression and medial prefrontal cortex (mPFC) glutamate as consequences of withdrawal from intermittent access to EtOH. These studies reveal aggressive behavior as a novel symptom of EtOH withdrawal in outbred mice and confirm a role of NMDARs during withdrawal aggression and for disrupted social behavior.
SOCIAL DEFEAT STRESS-INDUCED SENSITIZATION AND ESCALATED COCAINE SELF-ADMINISTRATION: THE ROLE OF ERK SIGNALING IN THE RAT VENTRAL TEGMENTAL AREA
Yap JJ, Chartoff EH, Holly EN, Carlezon Jr WA, Miczek KA
Social defeat stress induces neuroadaptations that can promote compulsive drug taking. Repeated cocaine administration activates extracellular signal-related kinase (ERK) in mesolimbic circuitry, so here we investigated whether stress-induced changes in ERK phosphorylation are necessary for the behavioral and neural adaptation to cocaine. We find that enhanced activation of ERK in the ventral tegmental area during social stress is critical for escalated cocaine self-administration.
INDIVIDUAL DIFFERENCES IN ANHEDONIC AND ACCUMBAL DOPAMINE RESPONSES TO CHRONIC SOCIAL STRESS AND THEIR LINK TO COCAINE SELF-ADMINISTRATION IN FEMALE RATS
Shimamoto A, Holly EN, Boyson CO, DeBold JF, Miczek KA
Women are twice as likely as men to develop major depressive disorder (MDD), which has a high comborbidity with substance use disorders. Chronic stress is a potent risk factor for MDD, but there are substantial individual differences in the response to chronic stress, such that some vulnerable individuals develop MDD while others are resistant. Here, we examined individual differences in behavioral and neural responses to cocaine in female rats that underwent chronic social defeat stress.
BLUNTED ACCUMBAL DOPAMINE RESPONSE TO COCAINE FOLLOWING CHRONIC SOCIAL STRESS IN FEMALE RATS: EXPLORING A LINK BETWEEN DEPRESSION AND DRUG ABUSE
Shimamoto A, DeBold JF, Holly EN, Miczek KA
Women are twice as likely as men to develop major depressive disorder (MDD), and it is estimated that approximately a quarter of these women also show comorbid substance use disorders. Here, we established a new method of chronic social defeat stress in female rats which produces some cardinal features of MDD. We further found that female rats undergoing chronic social defeat show blunted dopaminergic responses to cocaine, which may underlie comorbidities with substance use disorders.
THE NEUROTENSIN-1 RECEPTOR AGONIST PD149163 INHIBITS CONDITIONED AVOIDANCE RESPONDING WITHOUT PRODUCING CATALEPSY IN RATS
European Neuropsychopharmacology (2011)
Holly EN, Ebrecht B, Prus AJ
Schizophrenia is a debilitating psychiatric disorder, yet typical antipsychotic drugs have very limited efficacy. Here, we characterize a neurotensin-1 receptor agonist (PD149163), a putative new atypical antipsychotic drug. We found PD149163 decreases conditioned avoidance responses, a highly validated task for screening antipsychotic drugs. Typical antipsychotic drugs also commonly cause motor deficits, or extrapyramidal side effects. PD149163 did not cause catalepsy or other significant motor disturbances.