Midbrain dopamine (DA) neurons are central to reward processes and the development of drug addiction. Changes in their firing rate appear to encode the value of a stimulus;desirable substances or stimuli (e.g. food, water, and addictive drugs) elevate the firing of these neurons while undesirable substances or stimuli (e.g. mild shock, drug withdrawal) inhibit the same neurons. Until recently, the source of such inhibition was unknown. It is now hypothesized that glutamatergic neurons in the lateral habenula (LHb), a phylogenetically conserved part of the epithalamus, are responsible for such inhibition. However, because LHb neurons are excitatory there must be intervening inhibitory GABA neurons that, when excited by the LHb, decrease the firing rate of DA neurons. While there are GABA neurons in close proximity to the DA neurons, there are too few to account for the widespread inhibition of DA neurons observed. A newly described nucleus, the mesopontine rostromedial tegmental nucleus (RMTg) appears to have the required characteristics to fulfill this role;it is comprised almost solely of GABA neurons, receives heavy inputs from the LHb, and projects heavily to midbrain DA neurons. The central goal of this application is to test the role the RMTg may play in the transmission of aversive signals to midbrain DA neurons. Slice recording of DA cells following electrical stimulation of the LHb outputs, conditions that normally lead to widespread inhibition of DA neurons, will be conducted. Dissection of the RMTg from the slice preparation will test whether this area is necessary for the appearance of such inhibition (Specific Aim 1). We will look at activation of the RMTg by detection of the immediate early transcription factor c-Fos in response to aversive stimuli both with and without input from the LHb (Specific Aim 2). Finally, we will test whether the presence of the RMTg is necessary for LHb stimulation to induce conditioned place aversion, which is the avoidance of a specific environment that have been paired with an aversive stimulus, and reduce the ability of cocaine to induce conditioned place preference (Specific Aim 3). It is anticipated that the proposed research will elucidate the influence aversive stimuli have on the neurocircuitry of reward. Such information will help us to understand why individuals may relapse into drug use, despite the negative side effects of continued use, and to develop new approaches to the treatment of drug addiction.
The activation of dopamine (DA) is heavily implicated in the reward process and the development of addiction. However how the brain inhibits DA activity, potentially decreasing the value of rewarding substance and applying a brake to the reward process, is not well understood. Here we investigate a newly described brain circuit that may be responsible for inhibition of DA neurons. Such research will help us to understand why some individuals are more susceptibility to drug addiction and the propensity of former drug users to return to drug use.
|Brown, P Leon; Palacorolla, Heather; Brady, Dana et al. (2017) Habenula-Induced Inhibition of Midbrain Dopamine Neurons Is Diminished by Lesions of the Rostromedial Tegmental Nucleus. J Neurosci 37:217-225|
|Brown, P Leon; Shepard, Paul D (2016) Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat. J Neurophysiol 116:1161-74|
|Brown, Paul Leon; Shepard, Paul D (2013) Lesions of the fasciculus retroflexus alter footshock-induced cFos expression in the mesopontine rostromedial tegmental area of rats. PLoS One 8:e60678|