The mesocorticolimbic DA system has been primarily implicated in the reinforcing effects of drugs of abuse. While this pathway and DA signaling are the focus of most research in this area, it is also clear that NE, via interactions with the stress and DA systems, plays an important role in modulating the neurochemical and behavioral responses to drugs of abuse. We are currently determining the neurocircuitry and neurochemistry underlying the requirement of NE for reinstatement of drug seeking, a model of relapse. We are also examining how chronic loss of NE transmission, via genetic or pharmacologic means, alters the response of nucleus accumbens neurons to drugs of abuse via compensatory changes in a scaffolding and signal transduction protein called beta-arrestin2. Finally, we have developed a novel model of stress-induced reinstatement that utilizes social defeat rather than the canonical footshock paradigm to more closely resemble the type of psychosocial stress that leads to relapse in humans. We are currently identifying and testing the neuroanatomical substrates underlying this relapse modality.
Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by the beta-amyloid plaques and tau neurofibrillary tangles. A ubiquitous but less recognized feature of AD is the loss of noradrenergic neurons in the LC, and it is now recognized that the LC is among the earliest regions of the brain where pathogenic tau has been detected. We are currently pursuing 3 different approaches to characterize the role of the LC in AD. First, we are using primary LC neuron cultures to determine how tau expression affects neuronal survival and morphology, as well as the susceptibility of these cells to toxic insults. Second, we have generated a new transgenic mouse that expresses human tau exclusively in LC neurons to assess the potential spread of tau pathology from the LC to connected forebrain regions over time (i.e. “seeding”). Finally, we are using a transgenic rat model of AD to determine whether optogenetic/chemogenetic activation of LC neurons can ameliorate neuropathology and cognitive deficits.
LC activity fluctuates with sleep-wake cycles, and the LC is classically implicated in promoting arousal. However, the circuits underlying the wake-promoting effects of LC activity have not been identified. We are currently using DREADDs, knockout mice that lack NE, and receptor agonists/antagonists to investigate potential interactions between the LC and an understudied population of DA neurons in the ventral periaqueductal gray that may increase arousal.
Depression and Post Traumatic Stress Disorder
LC hyperactivity has been implicated in depression in both humans and animal models of both depression and PTSD, but a direct causal relationship has not been established. We are using chemogenetic and optogenetic approaches to specifically control LC activity and assess effects on behavior. We are also using conditional knockout mice and pharmacology to assess the relative contribution of NE and the LC co-transmitter neuropeptide galanin.