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Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake

Melani, Riccardo; Tritsch, Nicolas X
Dopamine (DA)-releasing neurons in the substantia nigra pars compacta (SNcDA) inhibit target cells in the striatum through postsynaptic activation of γ-aminobutyric acid (GABA) receptors. However, the molecular mechanisms responsible for GABAergic signaling remain unclear, as SNcDA neurons lack enzymes typically required to produce GABA or package it into synaptic vesicles. Here, we show that aldehyde dehydrogenase 1a1 (Aldh1a1), an enzyme proposed to function as a GABA synthetic enzyme in SNcDA neurons, does not produce GABA for synaptic transmission. Instead, we demonstrate that SNcDA axons obtain GABA exclusively through presynaptic uptake using the membrane GABA transporter Gat1 (encoded by Slc6a1). GABA is then packaged for vesicular release using the vesicular monoamine transporter Vmat2. Our data therefore show that presynaptic transmitter recycling can substitute for de novo GABA synthesis and that Vmat2 contributes to vesicular GABA transport, expanding the range of molecular mechanisms available to neurons to support inhibitory synaptic communication.
PMID: 35443174
ISSN: 2211-1247
CID: 5217212

Dopamine differentially modulates the size of projection neuron ensembles in the intact and dopamine-depleted striatum

Maltese, Marta; March, Jeffrey R; Bashaw, Alexander G; Tritsch, Nicolas X
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.
PMID: 33983121
ISSN: 2050-084x
CID: 4867642

How alcohol affects motor control: not your usual suspects

Melani, Riccardo; Tritsch, Nicolas X
PMID: 33758418
ISSN: 2522-5812
CID: 4822692

Posterior amygdala regulates sexual and aggressive behaviors in male mice

Yamaguchi, Takashi; Wei, Dongyu; Song, Soomin C; Lim, Byungkook; Tritsch, Nicolas X; Lin, Dayu
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 PAEsr1+ cells are activated during mating and are necessary and sufficient for male sexual behaviors, while VMHvl-projecting PAEsr1+ 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.
PMID: 32719562
ISSN: 1546-1726
CID: 4540192

A Hypothalamic Midbrain Pathway Essential for Driving Maternal Behaviors

Fang, Yi-Ya; Yamaguchi, Takashi; Song, Soomin C; Tritsch, Nicolas X; Lin, Dayu
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 MPOAEsr1+cells impairs those behaviors, whereas optogenetic activation induces immediate pup retrieval. In vivo recordings demonstrate preferential activation of MPOAEsr1+cells during maternal behaviors and changes in MPOA cell responses across reproductive states. Furthermore, channelrhodopsin-assisted circuit mapping reveals a strong inhibitory projection from MPOAEsr1+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.
PMID: 29621487
ISSN: 1097-4199
CID: 3025802

Mechanisms and functions of GABA co-release

Tritsch, Nicolas X; Granger, Adam J; Sabatini, Bernardo L
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.
PMID: 26865019
ISSN: 1471-0048
CID: 1964622

Parkinson's Disease: A Thalamostriatal Rebalancing Act?

Tritsch, Nicolas X; Carter, Adam G
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.
PMID: 26889806
ISSN: 1097-4199
CID: 1949782

Multiphasic modulation of cholinergic interneurons by nigrostriatal afferents

Straub, Christoph; Tritsch, Nicolas X; Hagan, Nellwyn A; Gu, Chenghua; Sabatini, Bernardo L
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.
PMID: 24948810
ISSN: 1529-2401
CID: 1790742

Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis

Tritsch, Nicolas X; Oh, Won-Jong; Gu, Chenghua; Sabatini, Bernardo L
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:
PMID: 24843012
ISSN: 2050-084x
CID: 1790752

A direct projection from mouse primary visual cortex to dorsomedial striatum

Khibnik, Lena A; Tritsch, Nicolas X; Sabatini, Bernardo L
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.
PMID: 25141172
ISSN: 1932-6203
CID: 1790762