Faculty Bibliography

Dopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. Here, we use two-photon Ca²⁺ imaging to monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) simultaneously in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that increasing and decreasing DA biases striatal activity towards the direct and indirect pathways, respectively, by changing the overall number of SPNs recruited during behavior in a manner not predicted by existing models of DA function. This modulation is drastically altered in a model of Parkinson's disease. Our results reveal a previously unappreciated population-level influence of DA on striatal output and provide novel insights into the pathophysiology of Parkinson's disease.

Sexual and aggressive behaviors are fundamental to animal survival and reproduction. The medial preoptic nucleus (MPN) and ventrolateral part of the ventromedial hypothalamus (VMHvl) are essential regions for male sexual and aggressive behaviors, respectively. While key inhibitory inputs to the VMHvl and MPN have been identified, the extrahypothalamic excitatory inputs essential for social behaviors remain elusive. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the posterior amygdala (PA) as a main source of excitatory inputs to the hypothalamus and key mediators for mating and fighting in male mice. We find two largely distinct PA subpopulations that differ in connectivity, gene expression, in vivo responses and social behavior relevance. MPN-projecting PA^Esr1+ cells are activated during mating and are necessary and sufficient for male sexual behaviors, while VMHvl-projecting PA^Esr1+ cells are excited during intermale aggression and promote attacks. These findings place the PA as a key node in both male aggression and reproduction circuits.

Maternal behaviors are essential for the survival of the young. Previous studies implicated the medial preoptic area (MPOA) as an important region for maternal behaviors, but details of the maternal circuit remain incompletely understood. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the MPOA as key mediators of pup approach and retrieval. Reversible inactivation of MPOA^Esr1+cells impairs those behaviors, whereas optogenetic activation induces immediate pup retrieval. In vivo recordings demonstrate preferential activation of MPOA^Esr1+cells during maternal behaviors and changes in MPOA cell responses across reproductive states. Furthermore, channelrhodopsin-assisted circuit mapping reveals a strong inhibitory projection from MPOA^Esr1+cells to ventral tegmental area (VTA) non-dopaminergic cells. Pathway-specific manipulations reveal that this projection is essential for driving pup approach and retrieval and that VTA dopaminergic cells are reliably activated during those behaviors. Altogether, this study provides new insight into the neural circuit that generates maternal behaviors.

The 'one neuron, one neurotransmitter' doctrine states that synaptic communication between two neurons occurs through the release of a single chemical transmitter. However, recent findings suggest that neurons that communicate using more than one classical neurotransmitter are prevalent throughout the adult mammalian CNS. In particular, several populations of neurons previously thought to release only glutamate, acetylcholine, dopamine or histamine also release the major inhibitory neurotransmitter GABA. Here, we review these findings and discuss the implications of GABA co-release for synaptic transmission and plasticity.

Motor impairments in Parkinson's disease are thought to result from hypoactivation of striatal projection neurons in the direct pathway. In this issue of Neuron, Parker et al. (2016) report that dopamine depletion selectively weakens thalamic but not cortical afferents onto these neurons, implicating the thalamus as playing a key role in Parkinsonian motor symptoms.

The motor and learning functions of the striatum are critically dependent on synaptic transmission from midbrain dopamine neurons and striatal cholinergic interneurons (CINs). Both neural populations alter their discharge in vivo in response to salient sensory stimuli, albeit in opposite directions. Whereas midbrain dopamine neurons respond to salient stimuli with a brief burst of activity, CINs exhibit a distinct pause in firing that is often followed by a period of increased excitability. Although this "pause-rebound" sensory response requires dopaminergic signaling, the precise mechanisms underlying the modulation of CIN firing by dopaminergic afferents remain unclear. Here, we show that phasic activation of nigrostriatal afferents in a mouse striatal slice preparation is sufficient to evoke a pause-rebound response in CINs. Using a combination of optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that synaptically released dopamine inhibits CINs through type 2 dopamine receptors, while another unidentified transmitter mediates the delayed excitation. These findings imply that, in addition to their direct effects on striatal projection neurons, midbrain dopamine neurons indirectly modulate striatal output by dynamically controlling cholinergic tone. In addition, our data suggest that phasic dopaminergic activity may directly participate in the characteristic pause-rebound sensory response that CINs exhibit in vivo in response to salient and conditioned stimuli.

Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors.DOI: http://dx.doi.org/10.7554/eLife.01936.001.

The mammalian striatum receives inputs from many cortical areas, but the existence of a direct axonal projection from the primary visual cortex (V1) is controversial. In this study we use anterograde and retrograde tracing techniques to demonstrate that V1 directly innervates a topographically defined longitudinal strip of dorsomedial striatum in mice. We find that this projection forms functional excitatory synapses with direct and indirect pathway striatal projection neurons (SPNs) and engages feed-forward inhibition onto these cells. Importantly, stimulation of V1 afferents is sufficient to evoke phasic firing in SPNs. These findings therefore identify a striatal region that is functionally innervated by V1 and suggest that early visual processing may play an important role in striatal-based behaviors.

The substantia nigra pars compacta and ventral tegmental area contain the two largest populations of dopamine-releasing neurons in the mammalian brain. These neurons extend elaborate projections in the striatum, a large subcortical structure implicated in motor planning and reward-based learning. Phasic activation of dopaminergic neurons in response to salient or reward-predicting stimuli is thought to modulate striatal output through the release of dopamine to promote and reinforce motor action. Here we show that activation of dopamine neurons in striatal slices rapidly inhibits action potential firing in both direct- and indirect-pathway striatal projection neurons through vesicular release of the inhibitory transmitter GABA (gamma-aminobutyric acid). GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT. Instead, GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for dopamine. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Thus, these findings expand the repertoire of synaptic mechanisms used by dopamine neurons to influence basal ganglia circuits, show a new substrate whose transport is dependent on VMAT2 and demonstrate that GABA can function as a bona fide co-transmitter in monoaminergic neurons.