Extrinsic Sources of Cholinergic Innervation of the Striatal Complex: A Whole-Brain Mapping Analysis

Abstract

Acetylcholine in the striatal complex plays an important role in normal behavior and is affected in a number of neurological disorders. Although early studies suggested that acetylcholine in the striatum (STR) is derived almost exclusively from cholinergic interneurons (CIN), recent axonal mapping studies using conditional anterograde tracing have revealed the existence of a prominent direct cholinergic pathway from the pedunculopontine and laterodorsal tegmental nuclei to the dorsal striatum and nucleus accumbens. The identification of the importance of this pathway is essential for creating a complete model of cholinergic modulation in the striatum, and it opens the question as to whether other populations of cholinergic neurons may also contribute to such modulation. Here, using novel viral tracing technologies based on phenotype-specific fluorescent reporter expression in combination with retrograde tracing, we aimed to define other sources of cholinergic innervation of the striatum. Systematic mapping of the projections of all cholinergic structures in the brain (Ch1 to Ch8) by means of conditional tracing of cholinergic axons, revealed that the only extrinsic source of cholinergic innervation arises in the brainstem pedunculopontine and laterodorsal tegmental nuclei. Our results thus place the pedunculopontine and laterodorsal nuclei in a key and exclusive position to provide extrinsic cholinergic modulation of the activity of the striatal systems.

The Input-Output Relationship of the Cholinergic Basal Forebrain

“…The inputs from cortex are spatially sparse, a pattern also seen when cholinergic afferents are mapped without regard for output specificity (Do et al, 2016; Hu et al, 2016). Thus for simplicity we categorized all cortical areas into either isocortex, mesocortex, or allocortex according to McGeorge and Faull, 1989 (see classification scheme in Supplemental Table).…”

“…Monosynaptic viral tracing of neuromodulatory systems has been used in the noradrenergic, dopaminergic and serotonergic systems (Beier et al, 2015; Faget et al, 2016; Lerner et al, 2015; Ogawa et al, 2014; Pollak Dorocic et al, 2014; Schwarz et al, 2015; Watabe-Uchida et al, 2012; Weissbourd et al, 2014). BFc monosynaptic tracing was also reported (Do et al, 2016; Hu et al, 2016) though without reference to target specificity. Here we sample monosynaptic inputs from across the brain to gain insight into the networks able to control cholinergic innervation of different cortical regions and the amygdala.…”

Neurochemical organization of the ventral striatum’s olfactory tubercle

“…Cholinergic input to the OT arrives from the horizontal limb of the nucleus of the diagonal band of Broca, nucleus basalis of Meynert (nbM) as well as the laterodorsal tegmentum and the pedunclopontine nuclei in the brainstem (Dautan et al, ; Koulousakis, Andrade, Visser‐Vandewalle, & Sesia, ; Lauterborn, Isackson, Montalvo, & Gall, ; Mesulam, Mufson, Wainer, & Levey, ). Specifically, neurons from the horizontal limb of the nucleus of diagonal band of Broca project throughout the ventral striatum, but vertical limb neurons appear to selectively target the OT (Dautan, Hacioğlu, Bolam, Gerdjikov, & Mena‐Segovia, ).…”

Neuroplasticity in cholinergic neurons of the laterodorsal tegmental nucleus contributes to the development of cocaine addiction

“…The LDT consists of cholinergic, glutamatergic, and GABAergic neurons and these three neuronal groups do not appear to exhibit any overlap (Wang & Morales, ). The LDT sends efferent projections to a variety of brain regions such as the ventral tegmental area (VTA), thalamus, nucleus accumbens (NAc), hypothalamus, ventral pallidum, and amygdala, and cholinergic neurons innervate most of these target brain regions of the LDT (Cornwall et al ., ; Oakman et al ., ; Holmstrand & Sesack, ; Dautan et al ., , ,). The LDT, as well as the adjacently located caudal part of the pedunculopontine nucleus (PPN), is the primary source of cholinergic input to the VTA, while rostral part of the PPN mainly projects to the substantia nigra pars compacta (Clarke et al ., ; Bolam et al ., ; Oakman et al ., ; Mena‐Segovia et al ., ; Holmstrand & Sesack, ).…”