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1.
Neuron ; 111(19): 3102-3118.e7, 2023 10 04.
Article in English | MEDLINE | ID: mdl-37499661

ABSTRACT

GABAergic neurons in the laterodorsal tegmental nucleus (LDTGABA) encode aversion by directly inhibiting mesolimbic dopamine (DA). Yet, the detailed cellular and circuit mechanisms by which these cells relay unpleasant stimuli to DA neurons and regulate behavioral output remain largely unclear. Here, we show that LDTGABA neurons bidirectionally respond to rewarding and aversive stimuli in mice. Activation of LDTGABA neurons promotes aversion and reduces DA release in the lateral nucleus accumbens. Furthermore, we identified two molecularly distinct LDTGABA cell populations. Somatostatin-expressing (Sst+) LDTGABA neurons indirectly regulate the mesolimbic DA system by disinhibiting excitatory hypothalamic neurons. In contrast, Reelin-expressing LDTGABA neurons directly inhibit downstream DA neurons. The identification of separate GABAergic subpopulations in a single brainstem nucleus that relay unpleasant stimuli to the mesolimbic DA system through direct and indirect projections is critical for establishing a circuit-level understanding of how negative valence is encoded in the mammalian brain.


Subject(s)
Dopamine , Ventral Tegmental Area , Mice , Animals , Ventral Tegmental Area/physiology , Dopamine/physiology , Nucleus Accumbens , Dopaminergic Neurons/physiology , gamma-Aminobutyric Acid , Mammals
2.
Neuron ; 110(18): 3018-3035.e7, 2022 09 21.
Article in English | MEDLINE | ID: mdl-35921846

ABSTRACT

Nicotine stimulates the dopamine (DA) system, which is essential for its rewarding effect. Nicotine is also aversive at high doses; yet, our knowledge about nicotine's dose-dependent effects on DA circuits remains limited. Here, we demonstrate that high doses of nicotine, which induce aversion-related behavior in mice, cause biphasic inhibitory and excitatory responses in VTA DA neurons that can be dissociated by distinct projections to lateral and medial nucleus accumben subregions, respectively. Guided by computational modeling, we performed a pharmacological investigation to establish that inhibitory effects of aversive nicotine involve desensitization of α4ß2 and activation of α7 nicotinic acetylcholine receptors. We identify α7-dependent activation of upstream GABA neurons in the laterodorsal tegmentum (LDT) as a key regulator of heterogeneous DA release following aversive nicotine. Finally, inhibition of LDT GABA terminals in VTA prevents nicotine aversion. Together, our findings provide a mechanistic circuit-level understanding of nicotine's dose-dependent effects on reward and aversion.


Subject(s)
Nicotine , Receptors, Nicotinic , Animals , Dopamine/physiology , Dopaminergic Neurons/metabolism , Mice , Nicotine/pharmacology , Receptors, Nicotinic/metabolism , Ventral Tegmental Area/physiology , alpha7 Nicotinic Acetylcholine Receptor , gamma-Aminobutyric Acid/pharmacology
3.
J Physiol ; 592(4): 711-27, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-24366258

ABSTRACT

Most cells maintain [Ca(2+)]i at extremely low levels; calcium entry usually occurs briefly, and within seconds it is cleared. However, at embryonic day 12.5 in the mouse brainstem, trains of spontaneous events occur with [Ca(2+)]i staying close to peak value, well above baseline, for minutes; we termed this 'bash bursts'. Here, we investigate the mechanism of this unusual activity using calcium imaging and electrophysiology. Bash bursts are triggered by an event originating at the mid-line of the rostral hindbrain and are usually the result of that event propagating repeatedly along a defined circular path. The looping circuit can either encompass both the midbrain and hindbrain or remain in the hindbrain only, and the type of loop determines the duration of a single lap time, 5 or 3 s, respectively. Bash bursts are supported by high membrane excitability of mid-line cells and are regulated by persistent inward 'window current' at rest, contributing to spontaneous activity. This looping circuit is an effective means for increasing [Ca(2+)]i at brief, regular intervals. Bash bursts disappear by embryonic day 13.5 via alteration of the looping circuit, curtailing the short epoch of bash bursts. The resulting sustained [Ca(2+)]i may influence development of raphe serotonergic and ventral tegmental dopaminergic neurons by modulating gene expression.


Subject(s)
Action Potentials , Brain Stem/physiology , Calcium Signaling , Calcium/metabolism , Animals , Brain Stem/embryology , Brain Stem/metabolism , Mice
4.
J Physiol ; 591(4): 973-83, 2013 Feb 15.
Article in English | MEDLINE | ID: mdl-23165771

ABSTRACT

Abstract Spontaneous activity supports developmental processes in many brain regions during embryogenesis, and the spatial extent and frequency of the spontaneous activity are tightly regulated by stage. In the developing mouse hindbrain, spontaneous activity propagates widely and the waves can cover the entire hindbrain at E11.5. The activity then retracts to waves that are spatially restricted to the rostral midline at E13.5, before disappearing altogether by E15.5. However, the mechanism of retraction is unknown. We studied passive membrane properties of cells that are spatiotemporally relevant to the pattern of retraction in mouse embryonic hindbrain using whole-cell patch clamp and imaging techniques. We find that membrane excitability progressively decreases due to hyperpolarization of resting membrane potential and increased resting conductance density between E11.5 and E15.5, in a spatiotemporal pattern correlated with the retraction sequence. Retraction can be acutely reversed by membrane depolarization at E15.5, and the induced events propagate similarly to spontaneous activity at earlier stages, though without involving gap junctional coupling. Manipulation of [K(+)](o) or [Cl(-)](o) reveals that membrane potential follows E(K) more closely than E(Cl), suggesting a dominant role for K(+) conductance in the membrane hyperpolarization. Reducing membrane excitability by hyperpolarization of the resting membrane potential and increasing resting conductance are effective mechanisms to desynchronize spontaneous activity in a spatiotemporal manner, while allowing information processing to occur at the synaptic and cellular level.


Subject(s)
Embryonic Development/physiology , Rhombencephalon/physiology , Animals , Calcium/physiology , In Vitro Techniques , Membrane Potentials , Mice , Potassium/physiology , Rhombencephalon/embryology
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