PUBLICATIONS

STRIATAL LOW-THRESHOLD SPIKING INTERNEURONS LOCALLY GATE DOPAMINE

Current Biology (in press)

Holly EN^, Davatolhagh MF, España RA, Fuccillo MV^

^co-corresponding authors

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

Neuron (2019)

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
*co-first authors

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
^corresponding author

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

Psychopharmacology (2016)

Holly EN^, Miczek KA

^corresponding author

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
^corresponding author

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

Psychopharmacology (2016)
Boyson CO*, Holly EN*, Burke AR, Montagud-Romero S, DeBold JF, Miczek KA
*co-first authors

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

Psychopharmacology (2015)
Holly EN^, DeBold JF, Miczek KA
^corresponding author

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.