DESCRIPTION (provided by applicant): Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) provide a critical modulation of limbic striatal and cortical targets that facilitates appropriate motor control, approach behaviors, motivation and cognition. Deficits in these forebrain dopamine systems are associated with mental health disorders such as schizophrenia, depression, attention deficit hyperactivity disorder and substance abuse. Hence, it is important to gain a clear understanding of how DA neuron activity is itself regulated. DA neurons fire tonically via pacemaker potentials, but important signals regarding future expectancy are generated by bursts and pauses in the activity pattern that are mediated by afferent drive. In our prior research, we examined excitatory afferents to VTA DA neurons from the prefrontal cortex. We discovered a surprising degree of specificity in these connections, in that prefrontal cortical afferents synapsed only onto DA neurons projecting back to the prefrontal cortex and not onto the more numerous DA cell population projecting to the nucleus accumbens. In the present proposal, we wish to address the likelihood of additional specificity in other synaptic inputs to these same DA neuron populations in the VTA that correlate with their activity levels and functions. This goal will be accomplished through the following five specific aims. We will examine both mesoprefrontal and mesoaccumbens DA neurons specifically for (1) their general excitatory and inhibitory drive as identified by glutamate and GABA in synaptic inputs, (2) specific excitatory afferents from the brainstem laterodorsal and pedunculopontine tegmentum, (3) extrinsically derived inhibitory afferents from the nucleus accumbens, (4) intrinsically derived inhibitory synapses from GABA neurons within the VTA, and (5) mixed/modulatory afferents from the lateral hypothalamus. Evidence consistent with selective afferent drive to different populations of DA neurons will provide valuable insight into the function of each cell group and the contributions they make to normal and abnormal behaviors. Evidence for selectivity in these afferents also has important implications for the development of specific pharmacological treatments for mental health disorders that involve these populations.