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3 Modeling Falls and Cognitive-Motor Deficits with Dual Cholinergic and Dopaminergic System Losses

3 Modeling Falls and Cognitive-Motor Deficits with Dual Cholinergic and Dopaminergic System Losses

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Cortico-Striatal, Cognitive-Motor Interactions Underlying Complex Movement…



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dynamic surfaces (rotating square rods; ten rotations per minute). Traversing rotating rods requires persistent attentional control of gait, limb coordination, and carefully timed and placed steps. To maintain cognitive challenge, rats were tested on a

battery of progressively demanding traversal conditions that included reversing and

alternating the direction of rotation of the rods, placing the rods at inclines up to 35°,

and incorporating passive and active distractors along the rods. Following baseline

training, rats were administered bilateral infusions of cholinergic-specific neurotoxin

192-IGg saporin into the nucleus basalis of Meynert (nbM) of the BF, which reliably

eliminates 50–90 % of cholinergic cell bodies in this region (Kucinski et al. 2013;

Kucinski and Sarter 2015). Dopamine terminals in the dorsomedial “associative” striatum were bilaterally lesioned with 6-hydroxydopamine (6-OHDA). Rats received both

types of lesions or lesions to either system alone. In addition to assessment of complex

movement and falls on the MCMCT, rats were tested on a sustained attention task.

The results indicated that falls from the rotating rods were moderately but significantly increased in rats with cholinergic BF lesions; however, falls were robustly

increased in rats with both cholinergic and striatal dopamine lesions (Duals, “DL”).

Falls in DL rats were consistently high across the rotating rod conditions; however,

impaired traversal performance in rats with BF lesions was revealed only in particularly complex trials (when the direction of the rotating rod was reversed from the

familiar direction). Striatal dopamine loss alone did not impair MCMCT performance, suggesting that compensatory attentional mechanisms contributed to the

prevention of falls in these animals.

We closely examined gait and posture characteristics of DL rats to determine possible risk factors for falls from the rotating rods. DL rats exhibited a number of gait and

posture abnormalities, such as slower traversal speed, less distance covered with each

step, slower stride cycle, an abnormal “slouched posture,” and lack of corrective movements following slips, such as active tail motion to regain balance. These risk factors for

falls are analogous to those observed in human PD fallers such as slow gait speed, insufficient recovery movements following slips, abnormal traversing posture, and reduced

step frequency (Grimbergen et al. 2004). Such deficits may reflect impairments in the

planning and sequencing of movements and, more generally, low “motor motivation”

caused primarily by the impact of striatal dopamine loss (Mazzoni et al. 2007).

Performance on the attentional task was similarly impaired in rats with BF lesions

and rats in DL rats, indicating that cholinergic loss alone impaired attentional performance and that striatal dopamine loss did not exacerbate such impairment (Kucinski

et al. 2013). Similar to MCMCT performance, rats with only striatal dopamine losses

had no deficits on the attention task, and actually performed better than sham rats on

one task condition. In DL rats, poor attentional performance correlated with fall rates

on the MCMCT. Quantitative histological analyses indicated that in DL rats, but not in

rats with dopaminergic deafferentation alone, larger and more precisely placed dorsomedial striatal dopamine loss predicted higher fall rates. Collectively, we interpreted

these findings as indicating that, in the presence of attentional control deficits, impairments in the striatal control of complex movements, gait, and balance resulting from

loss of dopamine are “unmasked,” causing gait and posture disturbances and falls.

From these findings we can describe a cognitive-motor circuitry model that

accounts for falls arising from loss of cortical acetylcholine and striatal dopamine

(see Fig. 6.1). When navigating complex surfaces such as stairs, or making sudden



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Fig. 6.1 Schematic illustration of the 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 the 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 falls, 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 innominata (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 (Luiten et al. 1987; Zaborszky et al. 2015). In prefrontal cortex (PFC), cholinergic neurons contact GABAergic

inhibitory interneurons and pyramidal cells and, as illustrated, both innervation patterns may contribute to cortico-striatal output. 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 or “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. 2007, 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 (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



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turns, or in rats traversing rotating rods, attention to cues related to dynamic surfaces and distractions as well as body posture, balance, gait control, and step placement are critical in guiding ongoing movement. With disruption of cortico-striatal

systems, particularly within the “associative” cortical-BG loop, there may be failure

to detect and process cues and rapidly integrate relevant information into ongoing

motor actions. In attentionally demanding situations, cholinergic transients report

the presence of cues to the striatum and thus, following cholinergic loss, the striatum may be largely deprived of information that normally reports the presence of

cues, including those normally detected and employed to support complex movement, such as limb placement onto a dynamic surface or slips that would normally

trigger corrective action.

Direct pathway projecting medium spiny neurons of the striatum that innervate

primarily the SNr and the GPi are contacted by prefrontal cortex efferents (Wall

et al. 2013) and are also modulated by ascending midbrain dopamine neurons via

D1 receptors on dendritic spines (Pickel et al. 1981). Dopamine thus selects certain cortico-striatal input over others and, therefore, dopaminergic deafferentation

may disrupt selection or filtering of cortical inputs (Bamford et al. 2004; Devan

et al. 1999; Guthrie et al. 2013; Kim et al. 2013; Strafella et al. 2005). Therefore,

loss of dopamine and cortical cholinergic input may additively impair striatal

function. In the context of ongoing complex movements, impaired cortico-striatal

input selection may therefore slow and even stop complex movement sequences

(Kim et al. 2013; e.g., Bhutani et al. 2013; Yin 2014), yielding the sensorimotor

risk factors for falls.

In older adults and PD patients, it is hypothesized that a major cause of falls is

the consumption of limited attentional resources by a secondary task, and thus withdrawal of such resources from supervising gait, balance, and complex movement

(Amboni et al. 2013; Plotnik et al. 2011; Tombu and Jolicoeur 2003; YogevSeligmann et al. 2013). In the presence of cholinergic cell loss and reduced attentional resources, additional taxation nearly abolishes the attentional monitoring of

motor action. As a result, gait freezes, postural imbalance, error-prone movements,

and eventually falls are more likely to occur (Uemura et al. 2012). With an intact

cholinergic system, performance errors activate the neuromodulatory component of

cortical cholinergic activity to enhance the detection of cues and errors to stabilize

and recover performance (St Peters et al. 2011).



6.4



Falls Resulting from Extensive Striatal Dopamine Loss



The majority of common movements, such as walking, are largely automatic, controlled by habitual motor pathways (Redgrave et al. 2010). Automation of learned

movement allows for focus on other cognitive operations and provides additional

attentional resources for recovery from unexpected movement errors, distractions,

and multitasking (Hikosaka and Isoda 2010). With aging and with loss of striatal

dopamine in PD, walking speed is reduced and there is less vigorous toe push-off,



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more step timing variability, smaller steps, decreased arm swing, forward bended

posture, and frontal plane instability (Bridenbaugh and Kressig 2011; Kurz et al.

2013; Marchese et al. 2003; Mazzoni et al. 2007; Winter et al. 1990). Dopamine loss

is known to slow responding and decrease accuracy in tasks involving habitual/

automatic responding or tasks requiring shifts between behavioral contingencies

(Baunez and Robbins 1999; Darvas and Palmiter 2009; Domenger and Schwarting

2008; Hauber and Schmidt 1994; Lex and Hauber 2010; Rogers et al. 2001). Thus,

in addition to falls that originate from the combined attentional-motoric deficits

described above, falls may result from relatively severe impairments in normally

habitual motor functions caused by striatal dopamine loss, especially when traversing dynamic surfaces (Cole et al. 2011; Wood et al. 2002; Woollacott and ShumwayCook 2002).

To assess the impact of large dopamine losses on fall propensity, more extensive 6-OHDA lesions that extended into the dorsolateral and dorsomedial striatum

were administered to rats. As in the previous experiment, rats performed traversals

with a progressively demanding battery of MCMCT conditions, including inclines

and reversing the direction of the rotating rod. These large dopamine lesions

increased falls and slowed traversal speed (Kucinski et al. 2015). Falls were characterized by frequent freezing episodes, defined as stoppages of forward traversal

movement for more than 1 s. Freezing episodes occurred both spontaneously (with

no obvious trigger) or following stepping errors. Despite these impairments, falls

were less frequent than falls in DL rats tested previously. In addition, large dopamine losses did not impair the ability to perform increasingly complex movements,

such as traversing the rotating rod when the direction of rotation was reversed, as

was the case in DL rats or rats with only BF cholinergic lesions. However, falls that

were triggered by a doorframe distractor, a distractor designed to model doorframeevoked freezing of gait episodes in PD patients (Cowie et al. 2012), were preceded

by longer periods of immobility and occurred earlier in the run compared to DL rats.

Thus, we hypothesized that falls in these two lesion models stemmed from different

cognitive-behavioral mechanisms—large dopamine lesions of the dorsal striatum

caused falling due to propensity of freezing forward movement, while dorsomedial

lesions combined with cortical cholinergic loss models falls resulting from impairments in attentional-motor interactions and complex movement control.

Freezing of gait (FOG), a sudden disturbance of gait, in which patients often feel

stuck with their feet being “glued to the floor,” occurs in 30–60 % of the PD patients.

FOG is common in challenging situations with increased “mental stress” (Giladi

and Hausdorff 2006) and can often be overcome by applying external tricks such as

visual or auditory cues (Nieuwboer et al. 1997). Freezing episodes can be triggered

by disruptions in gait rhythm control and symmetry, postural control, and step scaling as well as attentional shifts (Cowie et al. 2012; Plotnik et al. 2012). It was

hypothesized that subcortical regions may fail to “update” motor sets during ongoing task performance during freezing episodes (Chee et al. 2009), thus shifting

habitual-driven movement to goal-directed movement. Such a shift would necessitate an over-reliance on cortical networks to complete tasks normally handled by

automatic networks and reduce efficiency and delay movement responses (Hallett



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