Deficits or surfeits in motivated behavior are key features of numerous and often comorbid psychiatric illnesses. The Fox lab focuses on the neural mechanisms governing dysregulated motivation in substance abuse and stress disorders. We use multidisciplinary approaches bridging complex behavior, cell-type-specific transcriptomics, in vivo measurements, and cell-type and circuit-specific genetic manipulations.

Current Lab Projects

Identifying circuit-specific molecular mechanisms in fentanyl use and relapse

Neurons in the ventral tegmental area (VTA) and Nucleus Accumbens (NAc) play key roles in reward-seeking and are usurped in addiction. While most work has focused on dopaminergic projections from VTA to NAc, how opioids alter projections from NAc to VTA is largely unknown. The NAc to VTA connection deserves considerable attention since D1-MSN activity drives reward-seeking behavior, D1-MSNs directly modulate VTA neurons, and opioid receptors expressed specifically on D1-MSN to VTA synapses control dopamine release. Opioid-induced transcriptional changes in VTA neurons play an important role in opioid abuse and are likely sensitive to altered D1-MSN activity. However, no studies have examined transcriptional changes based on a specific synaptic input. It is further unknown if molecular adaptations in the VTA caused by D1-MSN activity alter dopamine release. We have adopted a technically innovative approach that combines next-generation single nuclei RNA sequencing with transsynaptic viral tagging to identify transcriptional changes based on synaptic input. RNAseq is a powerful tool for quantifying thousands of transcripts and can be used to identify changes in expression independent of a priori predictions.

We are currently profiling transcriptional changes in VTA neurons receiving D1-MSN input after fentanyl self-administration. We will then generate Cre-dependent viruses to manipulate our candidate molecules to block fentanyl self-administration and seeking. With in vivo fast-scan cyclic voltammetry, we are determining how fentanyl and molecular targets in VTA neurons influence NAc dopamine release after self-administration.

Identifying circuit-specific molecular mechanisms in stress vulnerability

VTA dopamine neurons mediate behavioral outcomes to chronic social defeat stress (CSDS), an effect driven in part by upstream locus coeruleus (LC) norepinephrine neurons. LC norepinephrine activates adrenergic receptors on VTA dopamine neurons to reverse maladaptive cellular hyperactivity and promote resilient behavioral outcomes. While both LC and VTA neurons are implicated in the pathophysiology of depressive disorders, no work has tested how norepinephrine release and regulation in the VTA are altered by CSDS or the vicarious chronic witness defeat stress (CWDS). There is a further lack of information on how this circuit is altered in stressed females, or how its function might be altered by serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant treatments. We will examine noradrenergic mechanisms of stress resilience within the LC to VTA circuit with LC-specific optogenetic stimulation, in vivo FSCV, neuropharmacology, and next-generation sequencing.

Establishing an improved mouse model for stress and opioid cross-sensitization

The dynamic interplay between stress and drug exposure whereby exposure to one increases the response to the other is usually termed “cross-sensitization”. Historically, most rodent cross-sensitization studies were restricted to rats, excluded females, or introduced confounds (pain, inflammation) that complicate stress and opioid cross-sensitization studies. Prior drug use is associated with increased risk for other psychiatric illness, but most cross-sensitization studies focus on stress’s effect on drug-taking behavior and leave out how drug-taking impacts stress-related behaviors.