Fig. 2.
Schematic illustration of essential neurocircuitry underlying attentional–motor interactions in the intact brain (a), and following the dual loss of basal forebrain cholinergic neurons and striatal dopamine (b) that is hypothesized to be essential for falls. The figure is not designed to provide a comprehensive illustration of known circuitry, including the synaptic organization within individual regions. Rather, it represents the major anatomical–functional interactions deduced from research in PD fallers and, to a lesser degree, older adults prone to fall, and in an animal model of PD falling (Kucinski et al., 2013). In the intact brain (a), cholinergic projections to the cortex arise from the nucleus basalis of Meynert (nbM), the substantia innominate (SI) and the horizontal nucleus of the diagonal band (HDB) of the basal forebrain. The precise origin of cholinergic projections in these regions depends on the cortical target region but all subregions contribute to cortical innervation (e.g., Luiten et al., 1987; Zaborszky et al., 2012, 2013). In prefrontal cortex (PFC), cholinergic neurons contact GABAergic inhibitory interneurons and pyramidal cells and, as illustrated, both innervation patterns may contribute to corticostriatal output. Muscarinic (m)AChRs may primarily mediate the effects of cholinergic activity on cortical output (e.g., Nelson et al., 2005). In the cortex, two types of cholinergic activity likely originate from separate neurons in the basal forebrain. First, as detailed in the main text, for certain cues to be detected, the cues need to evoke a brief cholinergic release event (“transient”; Howe et al., 2013). Furthermore, cue-evoked glutamate release from mediodorsal thalamic (MD) input is necessary but not sufficient to evoke such a cholinergic transient (Parikh et al., 2008, 2010). The exact mechanisms linking this glutamatergic–cholinergic transient interaction are unknown and the figure indicates a parsimonious direct contact at cholinergic terminals. Cholinergic transients are thought to be the primary source for cholinergic stimulation of prefrontal output. The second, neuromodulatory component of cholinergic activity influences glutamatergic–cholinergic transients via stimulation of α4β2* nAChR expressed by glutamatergic terminals (references above; see also Lambe et al., 2003) (Note that other thalamic inputs to cortical neurons are not shown). Cortical projections to medium spiny neurons (MSNs) in the striatum preferentially make contact at the head of spines that are also contacted, as illustrated, by dopaminergic afferents (DA) from the midbrain (CPu, caudate-putamen). In the rat model, converging dopamine loss and the functional impact of cholinergic deafferentation of prefrontal cortex for cortico-striatal function was found to be essential for generating high rates of falls. This finding primarily implicates dopamine D1 receptor-expressing MSNs of the direct projection pathway to the midbrain (SNr, substantia nigra, pars reticulata). As illustrated in (b), falling in older adults and, more severely, PD, is a result of striatal dopamine loss and cortical cholinergic deafferentation, yielding striatal circuitry that lacks information about the efficacy of gait, posture, and movement and that is impaired in selecting and sequencing motor actions, resulting in slow and reluctant movements or fails to initiate movement altogether (see main text).