# Cholinergic brainstem signaling in striatal circuits

> **NIH NIH R01** · RUTGERS THE STATE UNIV OF NJ NEWARK · 2021 · $32,051

## Abstract

Title: Cholinergic brainstem signaling in striatal circuits, PI: Juan Mena-Segovia
PROJECT SUMMARY
The striatum is the main input structure of the basal ganglia and it plays a central role in action reinforcement,
movement planning and execution of motor sequences. Two neuromodulators exert powerful control over
striatal neuronal circuits: dopamine and acetylcholine. These neuromodulatory systems are inextricably linked,
such that they are anatomically interconnected and reciprocally regulated. A significant number of neurological
disorders that affect the basal ganglia are associated with the dysregulation of one or both of these
neuromodulatory systems (e.g. Parkinson’s disease, Tourette syndrome). Understanding how these systems
are regulated and how they modulate each other is fundamental for understanding normal basal ganglia
function and how they are altered in the diseased brain.
Until recently, striatal acetylcholine was believed to originate exclusively from the striatal cholinergic
interneurons. However, we discovered an extrinsic source of acetylcholine to the striatum originating in the
pedunculopontine nucleus (PPN) and laterodorsal tegmental nucleus (LDT) of the brainstem. Dopamine, on
the other hand, originates from the midbrain and innervate large extents of the striatum, and the activity of
dopamine neurons is strongly modulated by the axon collaterals of cholinergic PPN/LDT neurons. Our
preliminary data using optogenetic tools show that PPN and LDT produce a robust and direct modulatory effect
on distinct types of striatal neurons, including cholinergic interneurons. Thus, PPN/LDT neurons are not only
able to modulate the activity of dopamine neurons that in turn project densely to the striatum, but they are also
capable of directly modulating striatal microcircuits. Our data thus suggest that the PPN and LDT are in a key
position to modulate striatal function.
The goal of the proposed studies is to characterize the anatomical organization and functional significance of
the brainstem cholinergic innervation of the striatum. First, we will identify the striatal domains that are
preferentially innervated by brainstem cholinergic axons and identify the subtypes of striatal neurons targeted
by PPN and LDT axons. Second, using optogenetic methods, we will characterize the impact of PPN and LDT
axons on neurochemically identified single striatal neurons. Third, we will identify the direct impact of the PPN
and LDT cholinergic neurons on striatal-dependent behaviors. Furthermore, because striatal cholinergic
interneurons and PPN/LDT cholinergic neurons are two markedly distinct populations in terms of their synaptic
inputs, intrinsic physiological properties and pattern of activation during behavior, we expect to see critical
differences in how they influence striatal circuits and striatal function. Thus, we will compare the anatomical
and physiological organization of these two sources of acetylcholine.
The discovery of an extrinsic s...

## Key facts

- **NIH application ID:** 10408254
- **Project number:** 3R01NS100824-05S1
- **Recipient organization:** RUTGERS THE STATE UNIV OF NJ NEWARK
- **Principal Investigator:** Juan MENA-SEGOVIA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $32,051
- **Award type:** 3
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10408254

## Citation

> US National Institutes of Health, RePORTER application 10408254, Cholinergic brainstem signaling in striatal circuits (3R01NS100824-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10408254. Licensed CC0.

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