Nicotinic Receptor Subtype-Selective Circuit Patterns in the Subthalamic Nucleus

Abstract

The glutamatergic subthalamic nucleus (STN) exerts control over motor output through nuclei of the basal ganglia. High-frequency electrical stimuli in the STN effectively alleviate motor symptoms in movement disorders, and cholinergic stimulation boosts this effect. To gain knowledge about the mechanisms of cholinergic modulation in the STN, we studied cellular and circuit aspects of nicotinic acetylcholine receptors (nAChRs) in mouse STN. We discovered two largely divergent microcircuits in the STN; these are regulated in part by either ␣4␤2 or ␣7 nAChRs. STN neurons containing ␣4␤2 nAChRs (␣4␤2 neurons) received more glutamatergic inputs, and preferentially innervated GABAergic neurons in the substantia nigra pars reticulata. In contrast, STN neurons containing ␣7 nAChRs (␣7 neurons) received more GABAergic inputs, and preferentially innervated dopaminergic neurons in the substantia nigra pars compacta. Interestingly, local electrical stimuli excited a majority (79%) of ␣4␤2 neurons but exerted strong inhibition in 58% of ␣7 neurons, indicating an additional diversity of STN neurons: responses to electrical stimulation. Chronic exposure to nicotine selectively affects ␣4␤2 nAChRs in STN: this treatment increased the number of ␣4␤2 neurons, upregulated ␣4-containing nAChR number and sensitivity, and enhanced the basal firing rate of ␣4␤2 neurons both ex vivo and in vivo. Thus, chronic nicotine enhances the function of the microcircuit involving ␣4␤2 nAChRs. This indicates chronic exposure to nicotinic agonist as a potential pharmacological intervention to alter selectively the balance between these two microcircuits, and may provide a means to inhibit substantia nigra dopaminergic neurons.

Optogenetic stimulation of cortico-subthalamic projections is sufficient to ameliorate bradykinesia in 6-ohda lesioned mice

“…However, the lack of preferential synapsing, or experimental differences such as the slower kinetics of the channel rhodopsin or the amount of opsin transfection present could have prevented direct STN stimulation from producing movement effects in that earlier study. It is also possible that in comparison to direct STN neuron activation, prodromic optogenetic cortical input stimulation more selectively targets subpopulations of STN neurons that respond strongly to cortical input such as the recently identified α4β2 nicotinic receptor containing neurons (Xiao et al, 2015). …”

Differential Control of Dopaminergic Excitability and Locomotion by Cholinergic Inputs in Mouse Substantia Nigra

“…The cholinergic input is likely from PPT and LDT as witnessed from other studies using anterograde tracing and optogenetics [7,19,25]. The glutamatergic input into the SNc is unknown but may be from the subthalamic nucleus [6], local glutamatergic SNc neurons [27], PPT glutamatergic neurons [14] or the somatosensory/motor cortices [28]. Cholinergic neurotransmission in the medial SNc largely involved indirect disynaptic GABAergic neurotransmission, mediated by GABAA receptors and presynaptic nAChRs (Fig.…”

“…As an integral component of the basal ganglia, DA neurons of the substantia nigra pars compacta (SNc) are key neural substrates for initiating voluntary movement. The activity of SNc neurons are modulated by several neurotransmitter systems including γ-aminobutyric acid (GABA), glutamate and acetylcholine (ACh) [4–6]. The major cholinergic input into the SNc are from two brainstem nuclei: the pedunculopontine tegmental nucleus (PPT) and the laterodorsal tegmental nucleus (LDT) [7,8].…”

Cholinergic Mesopontine Signals Govern Locomotion and Reward through Dissociable Midbrain Pathways

“…Electrophysiological recordings were performed on parasagittal brain slices, using the protocol described with some modifications (Xiao et al, 2015; Ye et al, 2006) (see supplementary materials). …”