Basal Forebrain Chemogenetic Inhibition Converts the Attentional Control Mode of Goal-Trackers to That of Sign-Trackers.

Sign tracking versus goal tracking in rats indicate vulnerability and resistance, respectively, to Pavlovian cue-evoked addictive drug taking and relapse. Here, we tested hypotheses predicting that the opponent cognitive-behavioral styles indexed by sign tracking versus goal tracking include variations in attentional performance which differentially depend on basal forebrain projection systems. Pavlovian Conditioned Approach (PCA) testing was used to identify male and female sign-trackers (STs) and goal-trackers (GTs), as well as rats with an intermediate phenotype (INTs). Upon reaching asymptotic performance in an operant task requiring the detection of visual signals (hits) as well as the reporting of signal absence for 40 min per session, GTs scored more hits than STs, and hit rates across all phenotypes correlated with PCA scores. STs missed relatively more signals than GTs specifically during the last 15 min of a session. Chemogenetic inhibition of the basal forebrain decreased hit rates in GTs but was without effect in STs. Moreover, the decrease in hits in GTs manifested solely during the last 15 min of a session. Transfection efficacy in the horizontal limb of the diagonal band (HDB), but not substantia innominate (SI) or nucleus basalis of Meynert (nbM), predicted the behavioral efficacy of chemogenetic inhibition in GTs. Furthermore, the total subregional transfection space, not transfection of just cholinergic neurons, correlated with performance effects. These results indicate that the cognitive-behavioral phenotype indexed by goal tracking, but not sign tracking, depends on activation of the basal forebrain-frontal cortical projection system and associated biases toward top-down or model-based performance.

Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071.

RATIONALE: In addition to the disease-defining motor symptoms, patients with Parkinson's disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls. These dopamine (DA) replacement-resistant symptoms in part have been attributed to loss of basal forebrain (BF) cholinergic neurons and, in interaction with striatal dopamine (DA) loss, to the resulting disruption of the attentional control of balance and complex movements. Rats with dual cholinergic-DA losses ("DL rats") were previously demonstrated to model PD falls and associated impairments of gait and balance. OBJECTIVES: We previously found that the muscarinic M1-positive allosteric modulator (PAM) TAK-071 improved the attentional performance of rats with BF cholinergic losses. Here, we tested the hypotheses that TAK-071 reduces fall rates in DL rats. RESULTS: Prior to DL surgery, female rats were trained to traverse a rotating straight rod as well as a rod with two zigzag segments. DL rats were refamiliarized with such traversals post-surgery and tested over 7 days on increasingly demanding testing conditions. TAK-071 (0.1, 0.3 mg/kg, p.o.) was administered prior to daily test sessions over this 7-day period. As before, DL rats fell more frequently than sham-operated control rats. Treatment of DL rats with TAK-071 reduced falls from the rotating rod and the rotating zigzag rod, specifically when the angled part of the zigzag segment, upon entering, was at a steep, near vertical angle. CONCLUSIONS: TAK-071 may benefit complex movement control, specifically in situations which disrupt the patterning of forward movement and require the interplay between cognitive and motor functions to modify movement based on information about the state of dynamic surfaces, balance, and gait.

Make a Left Turn: Cortico-Striatal Circuitry Mediating the Attentional Control of Complex Movements.

BACKGROUND: In movement disorders such as Parkinson's disease (PD), cholinergic signaling is disrupted by the loss of basal forebrain cholinergic neurons, as well as aberrant activity in striatal cholinergic interneurons (ChIs). Several lines of evidence suggest that gait imbalance, a key disabling symptom of PD, may be driven by alterations in high-level frontal cortical and cortico-striatal processing more typically associated with cognitive dysfunction. METHODS: Here we describe the corticostriatal circuitry that mediates the cognitive-motor interactions underlying such complex movement control. The ability to navigate dynamic, obstacle-rich environments requires the continuous integration of information about the environment with movement selection and sequencing. The cortical-attentional processing of extero- and interoceptive cues requires modulation by cholinergic activity to guide striatal movement control. Cue-derived information is "transferred" to striatal circuitry primarily via fronto-striatal glutamatergic projections. RESULT: Evidence from parkinsonian fallers and from a rodent model reproducing the dual cholinergic-dopaminergic losses observed in these patients supports the main hypotheses derived from this neuronal circuitry-guided conceptualization of parkinsonian falls. Furthermore, in the striatum, ChIs constitute a particularly critical node for the integration of cortical with midbrain dopaminergic afferents and thus for cues to control movements. CONCLUSION: Procholinergic treatments that enhance or rescue cortical and striatal mechanisms may improve complex movement control in parkinsonian fallers and perhaps also in older persons suffering from gait disorders and a propensity for falls. © 2021 International Parkinson and Movement Disorder Society.

Complex Movement Control in a Rat Model of Parkinsonian Falls: Bidirectional Control by Striatal Cholinergic Interneurons.

Older persons and, more severely, persons with Parkinson's disease (PD) exhibit gait dysfunction, postural instability and a propensity for falls. These dopamine (DA) replacement-resistant symptoms are associated with losses of basal forebrain and striatal cholinergic neurons, suggesting that falls reflect disruption of the corticostriatal transfer of movement-related cues and their striatal integration with movement sequencing. To advance a rodent model of the complex movement deficits of Parkinsonian fallers, here we first demonstrated that male and female rats with dual cortical cholinergic and striatal DA losses (DL rats) exhibit cued turning deficits, modeling the turning deficits seen in these patients. As striatal cholinergic interneurons (ChIs) are positioned to integrate movement cues with gait, and as ChI loss has been associated with falls in PD, we next used this task, as well as a previously established task used to reveal heightened fall rates in DL rats, to broadly test the role of ChIs. Chemogenetic inhibition of ChIs in otherwise intact male and female rats caused cued turning deficits and elevated fall rates. Spontaneous turning was unaffected. Furthermore, chemogenetic stimulation of ChIs in DL rats reduced fall rates and restored cued turning performance. Stimulation of ChIs was relatively more effective in rats with viral transfection spaces situated lateral to the DA depletion areas in the dorsomedial striatum. These results indicate that striatal ChIs are essential for the control of complex movements, and they suggest a therapeutic potential of stimulation of ChIs to restore gait and balance, and to prevent falls in PD.SIGNIFICANCE STATEMENT In persons with Parkinson's disease, gait dysfunction and the associated risk for falls do not benefit from dopamine replacement therapy and often result in long-term hospitalization and nursing home placement. Here, we first validated a new task to demonstrate impairments in cued turning behavior in rodents modeling the cholinergic-dopaminergic losses observed in Parkinsonian fallers. We then demonstrated the essential role of striatal cholinergic interneurons for turning behavior as well as for traversing dynamic surfaces and avoiding falls. Stimulation of these interneurons in the rat model rescued turning performance and reduced fall rates. Our findings indicate the feasibility of investigating the neuronal circuitry underling complex movement control in rodents, and that striatal cholinergic interneurons are an essential node of such circuitry.

Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071.

RATIONALE: Loss of basal forebrain cholinergic neurons contributes to the severity of the cognitive decline in age-related dementia and, in patients with Parkinson's disease (PD), to impairments in gait and balance and the resulting risks for falls. Contrasting with the extensive evidence indicating an essential role of cholinergic activity in mediating cognitive, specifically attentional abilities, treatment with conventional acetylcholinesterase inhibitors (AChEIs) has not fulfilled the promise of efficacy of pro-cholinergic treatments. OBJECTIVES: Here, we investigated the potential usefulness of a muscarinic M1 positive allosteric modulator (PAM) in an animal model of cholinergic loss-induced impairments in attentional performance. Given evidence indicating that fast, transient cholinergic signaling mediates the detection of cues in attentional contexts, we hypothesized that a M1 PAM amplifies such transient signaling and thereby rescues attentional performance. RESULTS: Rats performed an operant sustained attention task (SAT), including in the presence of a distractor (dSAT) and during a post-distractor (post-dSAT) period. The post-dSAT period served to assess the capacity for recovering performance following a disruptive event. Basal forebrain infusions of the cholino-specific immunotoxin 192 IgG-saporin impaired SAT performance, and greater cholinergic losses predicted lower post-dSAT performance. Administration of TAK-071 (0.1, 0.3 mg/kg, p.o., administered over 6-day blocks) improved the performance of all rats during the post-dSAT period (main effect of dose). Drug-induced improvement of post-dSAT performance was relatively greater in lesioned rats, irrespective of sex, but also manifested in female control rats. TAK-071 primarily improved perceptual sensitivity (d') in lesioned rats and facilitated the adoption of a more liberal response bias (B˝D) in all female rats. CONCLUSIONS: These findings suggest that TAK-071 may benefit the attentional performance of patients with partial cholinergic losses and specifically in situations that tax top-down, or goal-driven, attentional control.

Correction to: Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson's disease.

After publication of this paper, the authors determined that the "Acknowledgments" section was omitted. Below is the "Acknowledgments" statement.

Repetitive mild concussion in subjects with a vulnerable cholinergic system: Lasting cholinergic-attentional impairments in CHT+/- mice.

Previous research emphasized the impact of traumatic brain injury on cholinergic systems and associated cognitive functions. Here we addressed the converse question: Because of the available evidence indicating cognitive and neuronal vulnerabilities in humans expressing low-capacity cholinergic systems or with declining cholinergic systems, do injuries cause more severe cognitive decline in such subjects, and what cholinergic mechanisms contribute to such vulnerability? Using mice heterozygous for the choline transporter (CHT+/- mice) as a model for a limited cholinergic capacity, we investigated the cognitive and neuronal consequences of repeated, mild concussion injuries (rmCc). After five rmCc, and compared with wild type (WT) mice, CHT+/- mice exhibited severe and lasting impairments in sustained attention performance, consistent with effects of cholinergic losses on attention. However, rmCc did not affect the integrity of neuronal cell bodies and did not alter the density of cortical synapses. As a cellular mechanism potentially responsible for the attentional impairment in CHT+/- mice, we found that rmCc nearly completely attenuated performance-associated, CHT-mediated choline transport. These results predict that subjects with an already vulnerable cholinergic system will experience severe and lasting cognitive-cholinergic effects after even relatively mild injuries. If confirmed in humans, such subjects may be excluded from, or receive special protection against, activities involving injury risk. Moreover, the treatment and long-term outcome of traumatic brain injuries may benefit from determining the status of cholinergic systems and associated cognitive functions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Basal forebrain chemogenetic inhibition disrupts the superior complex movement control of goal-tracking rats.

Sign- and goal-tracking behavior signifies the influence of opposed cognitive-motivational styles, with the former being characterized by a tendency for approaching and contacting reward cues, including a readiness for attending, bottom-up, to salient cues, and a relatively greater vulnerability for developing and maintaining addiction-like behaviors. We previously demonstrated that these styles also impact the cognitive-motor interactions that are taxed during traversal of dynamic surfaces, with goal-trackers (GTs) making less movement errors and falling less frequently than sign-trackers (STs). The present experiment tested the hypothesis that complex movement control in GTs, but not STs, depends on activation of the basal forebrain projection system to telencephalic regions. Chemogenetic inhibition of the basal forebrain increased movement errors and falls in GTs during traversal of a rotating zigzag rod but had no significant effect on the relatively lower performance of STs. Neurochemical evidence confirmed the efficacy of the inhibitory designer receptor exclusively activated by designer drug (DREADD). Administration of clozapine-N-oxide (CNO) had no significant effect in GTs not expressing the DREADD. These results indicate that GTs, but not STs, activate the basal forebrain projection system to mediate their relatively superior ability for complex movement control. STs may also serve as an animal model in research on the role of basal forebrain systems in aging- and Parkinson's disease-associated falls. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson's disease.

RATIONALE: Falls in patients with Parkinson's disease (PD) are associated with cognitive, specifically attentional impairments and with losses in cholinergic projection systems. We previously established an animal model of the combined basal forebrain cholinergic-striatal dopaminergic losses of PD fallers (Dual Lesioned, DL, rats) and demonstrated that treating DL rats with an acetylcholinesterase inhibitor (AChEI), donepezil, together with a 5HT6 receptor antagonist, idalopirdine, reduced fall frequency and improved associated aspects of the performance of DL rats traversing rotating rods. OBJECTIVES: Here, we employed a longer and more taxing rotating beam apparatus to determine the potential therapeutic efficacy of idalopirdine when combined with the pseudo-irreversible, and thus relatively long-acting, AChE- and butyrylcholinesterase- (BuChE) inhibitor rivastigmine. RESULTS: As before, vehicle-treated DL rats fell more frequently, committed more slips, and exhibited more movement stoppages than intact control rats. Repeated intermittent administration of rivastigmine and idalopirdine significantly improved the performance of DL rats. Rivastigmine alone also produced strong trends for reducing falls and slips. The combination treatment was more effective than rivastigmine alone in reducing stoppages and stoppage-associated falls. As before, idalopirdine treatment alone was ineffective. CONCLUSIONS: These results extend the prediction that the combined treatment with idalopirdine and an AChEI improves complex movement control and reduces the propensity for falls in patients with movement disorders. Because of the importance of finding better treatments for gait and balance deficits in PD, the present results may further motivate a clinical exploration of the usefulness of this combination treatment.

Addiction vulnerability trait impacts complex movement control: Evidence from sign-trackers.

Cognitive-motivational vulnerability traits are associated with increased risk for substance addiction and relapse. Sign-tracking (ST) behavior in rats is associated with poor attentional control, mediated by an unresponsive basal forebrain cholinergic system, and an increased risk for substance addiction/relapse. A separate literature links poor attentional control and cholinergic losses to increased fall risk in Parkinson's disease. Here we tested the hypothesis that the relatively inferior attentional control of STs extends to complex movement control and a propensity for falls. STs were found to fall more often than goal-trackers (GTs) while traversing a straight rotating rod and, similar to human fallers, when taxed by a secondary task. Furthermore, STs fell more often while traversing a rotating zig-zag rod. GTs exhibited fewer falls from this rod by avoiding entry to the rotating zig-zag sections when in, or rotating toward, a difficult traversal state. Goal-tracking rats approached risky movement situations using strategies indicative of superior top-down control. These results suggest that the impact of opponent cognitive-cholinergic traits extends to complex movement control, and that impairments in the cognitive-motor interface are likely to be comorbid with addiction vulnerability. Sign-tracking indexes an endophenotype that may increase the risk for a wide range of neurobehavioral disorders.

Unresponsive Choline Transporter as a Trait Neuromarker and a Causal Mediator of Bottom-Up Attentional Biases.

Some rats [sign-trackers (STs)] are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane. Neither increases in choline uptake nor translocation of CHTs occurred in STs. Second, and consistent with uptake/translocation alterations, STs demonstrated a reduced ability to support cortical ACh release in vivo compared with GTs after reverse-dialysis to elevate extracellular potassium levels. Third, rats were significantly more likely to develop sign-tracking behavior if treated systemically before pavlovian conditioned approach training with the CHT inhibitor VU6001221. Consistent with its proposed mechanisms, administration of VU6001221 attenuated potassium-evoked ACh levels in prefrontal cortex measured with in vivo microdialysis. We propose that loss of CHT-dependent activation of cortical cholinergic activity in STs degrades top-down executive control over behavior, producing a bias for bottom-up or stimulus-driven attention. Such an attentional bias contributes to nonadaptive reward processing and thus identifies a novel mechanism that can support psychopathology, including addiction.SIGNIFICANCE STATEMENT The vulnerability for addiction-like behavior has been associated with psychological traits, such as the propensity to attribute incentive salience to reward cues that is modeled in rats by sign-tracking behavior. Sign-trackers tend to approach and contact cues associated with reward, whereas their counterparts, the goal-trackers, have a preference for approaching the location of the reward. Here, we show that the capacity of presynaptic cholinergic synapses to respond to stimulation by elevating presynaptic choline uptake and releasing acetylcholine is attenuated in sign-trackers. Furthermore, pharmacological inhibition of choline transport induced sign-tracking behavior. Our findings suggest that reduced levels of cholinergic neuromodulation can mediate an attentional bias toward reward-related cues, thereby allowing such cues to exert relatively greater control over behavior.

Reducing falls in Parkinson's disease: interactions between donepezil and the 5-HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements.

Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson's disease (PD), the leading levodopa-insensitive cause of hospitalization and long-term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic-dopaminergic losses ("DL rats") and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT6 receptor antagonist idalopirdine (Lu AE58054) was reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer's disease, here we assessed the effects of this treatment on MCMCT performance and attention in DL rats. Compared with the vehicle-treated group, the combined treatment greatly reduced (Cohen's d = 0.96) falls in DL rats when traversing dynamic surfaces and when exposed to a passive distractor. However, falls associated with a dual task distractor and sustained attentional performance did not benefit from this treatment. Analyses of the behavior in fall-prone moments suggested that this treatment improved the efficacy and speed of re-instating forward movement after relatively short stoppages. This treatment may reduce fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait.

Modeling Parkinson's disease falls associated with brainstem cholinergic systems decline.

In addition to the primary disease-defining symptoms, approximately half of patients with Parkinson's disease (PD) suffer from postural instability, impairments in gait control and a propensity for falls. Consistent with evidence from patients, we previously demonstrated that combined striatal dopamine (DA) and basal forebrain (BF) cholinergic cell loss causes falls in rats traversing dynamic surfaces. Because evidence suggests that degeneration of brainstem cholinergic neurons arising from the pedunculopontine nucleus (PPN) also contributes to impaired gait and falls, here we assessed the effects of selective cholinergic PPN lesions in combination with striatal DA loss or BF cholinergic cells loss as well as losses in all 3 regions. Results indicate that all combination losses that included the BF cholinergic system slowed traversal and increased slips and falls. However, the performance of rats with losses in all 3 regions (PPN, BF, and DA) was not more severely impaired than following combined BF cholinergic and striatal DA lesions. These results confirm the hypothesis that BF cholinergic-striatal disruption of attentional-motor interactions is a primary source of falls. Additional losses of PPN cholinergic neurons may worsen posture and gait control in situations not captured by the current testing conditions.

Modeling falls in Parkinson's disease: Slow gait, freezing episodes and falls in rats with extensive striatal dopamine loss.

Falls in patients with Parkinson's disease (PD) are a major and levodopa-unresponsive source of morbidity. We previously described an animal model of falls resulting from impairments in attentional-motor interactions. Reproducing the multisystem dopaminergic-cholinergic cell loss in patients with a history for falls, partial loss of striatal dopamine innervation interacted with loss of forebrain cholinergic neurons to generate falls that was hypothesized to reflect impairments in the attentional control of gait and balance and the sequencing of complex movements [1]. As clinical evidence also indicates that basal ganglia dopamine (DA) loss per se is associated with severe discoordination and thus a greater risk for falls, here we demonstrate that relatively extensive striatal DA loss, in contrast to the lack of effects of smaller, dorsal striatal DA losses and sham lesions, increased falls and slips and caused slowing while traversing dynamic surfaces. Falls in large DA rats were associated specifically with spontaneous or slip-triggered stoppages of forward movement. Collectively, the evidence suggests that low motivation or vigor for movement in general, and for initiating corrective movements in particular, are major sources for falls in rats with large DA losses. Falls are a result of complex cognitive-motor interactions, and rats with large DA losses model the impact of a propensity for freezing of gait when traversing dynamic surfaces.

The effects of varenicline on sensory gating and exploratory behavior with pretreatment with nicotinic or 5-HT3A receptor antagonists.

Individuals with schizophrenia smoke at high frequency relative to the general population. Despite the harmful effects of cigarette smoking, smoking among schizophrenic patients improves cognitive impairments not addressed or worsened by common neuroleptics. Varenicline, a nonselective neuronal nicotinic receptor (NNR) agonist and full agonist of 5-HT3A receptors, helps reduce smoking among schizophrenic patients. To determine whether varenicline also improves a cognitive symptom of schizophrenia, namely, impaired sensory gating, a transgenic mouse with schizophrenia, th-fgfr1(tk-), was used. Varenicline dose-dependently increased prepulse inhibition (PPI) of the startle response, a measure of sensory gating, in th-fgfr1(tk-) mice and normalized PPI deficits relative to nontransgenic controls. With the highest dose (10 mg/kg), however, there was a robust elevation of PPI and startle response, as well as reduced exploratory behavior in the open field and elevated plus maze. Pretreatment with the nonspecific NNR antagonist mecamylamine attenuated the exaggerated PPI response and, similar to the 5-HT3A receptor antagonist ondansetron, it prevented the reduction in exploratory behavior. Collectively, these results indicate that varenicline at low-to-moderate doses may be beneficial against impaired sensory gating in schizophrenia; however, higher doses may induce anxiogenic effects, which can be prevented with antagonists of NNRs or 5-HT3A receptors.

Where attention falls: Increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function.

Falls are a major source of hospitalization, long-term institutionalization, and death in older adults and patients with Parkinson's disease (PD). Limited attentional resources are a major risk factor for falls. In this review, we specify cognitive-behavioral mechanisms that produce falls and map these mechanisms onto a model of multi-system degeneration. Results from PET studies in PD fallers and findings from a recently developed animal model support the hypothesis that falls result from interactions between loss of basal forebrain cholinergic projections to the cortex and striatal dopamine loss. Striatal dopamine loss produces inefficient, low-vigor gait, posture control, and movement. Cortical cholinergic deafferentation impairs a wide range of attentional processes, including monitoring of gait, posture and complex movements. Cholinergic cell loss reveals the full impact of striatal dopamine loss on motor performance, reflecting loss of compensatory attentional supervision of movement. Dysregulation of dorsomedial striatal circuitry is an essential, albeit not exclusive, mediator of falls in this dual-system model. Because cholinergic neuromodulatory activity influences cortical circuitry primarily via stimulation of α4ß2* nicotinic acetylcholine receptors, and because agonists at these receptors are known to benefit attentional processes in animals and humans, treating PD fallers with such agonists, as an adjunct to dopaminergic treatment, is predicted to reduce falls. Falls are an informative behavioral endpoint to study attentional-motor integration by striatal circuitry.

Modeling fall propensity in Parkinson's disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation.

Cognitive symptoms, complex movement deficits, and increased propensity for falls are interrelated and levodopa-unresponsive symptoms in patients with Parkinson's disease (PD). We developed a test system for the assessment of fall propensity in rats and tested the hypothesis that interactions between loss of cortical cholinergic and striatal dopaminergic afferents increase fall propensity. Rats were trained to traverse stationary and rotating rods, placed horizontally or at inclines, and while exposed to distractors. Rats also performed an operant Sustained Attention Task (SAT). Partial cortical cholinergic and/or caudate dopaminergic deafferentation were produced by bilateral infusions of 192 IgG-saporin (SAP) into the basal forebrain and/or 6-hydroxydopamine (6-OHDA) into the caudate nucleus, respectively, modeling the lesions seen in early PD. Rats with dual cholinergic-dopaminergic lesions (DL) fell more frequently than SAP or 6-OHDA rats. Falls in DL rats were associated with incomplete rebalancing after slips and low traversal speed. Ladder rung walking and pasta handling performance did not indicate sensorimotor deficits. SAT performance was impaired in DL and SAP rats; however, SAT performance and falls were correlated only in DL rats. Furthermore, in DL rats, but not in rats with only dopaminergic lesions, the placement and size of dopaminergic lesion correlated significantly with fall rates. The results support the hypothesis that after dual cholinergic-dopaminergic lesions, attentional resources can no longer be recruited to compensate for diminished striatal control of complex movement, thereby "unmasking" impaired striatal control of complex movements and yielding falls.

Neuronal nicotinic receptor agonists ameliorate spontaneous motor asymmetries and motor discoordination in a unilateral mouse model of Parkinson's disease.

The degeneration of the nigrostriatal dopamine (DA) system underlies the motor deficits in Parkinson's disease (PD). In recent years, epidemiological reports that smokers have lower incidences of PD have brought attention to the nicotinic acetylcholine system as a potential target for novel therapeutics. Nicotine, an agonist of neuronal nicotinic receptors (NNRs), modulates functions relevant to PD via stimulation of dopaminergic transmission in the nigrostriatal pathway, particularly via activation of α6ß2* and α4ß2* NNRs. Recently, reduced support of DA neurons by neurotrophic growth factors has been described in PD. Fibroblast growth factor (FGF) is critical for the development and protection of adult DA neurons. In FGF-2 knockout mice and the related th-fgfr1(tk-) mouse model there is heightened sensitivity to DA neuronal oxidative neurotoxin 6-hydroxydopamine (6-OHDA). In the present study, FGF-deficient transgenic mice th-fgfr1(tk-) were used to analyze the effects of novel full (TC-8831) and partial (TC-8581) agonists of ß2-containing nicotinic receptors on impaired motor behavior following unilateral 6-OHDA lesions. The lesions generated spontaneous (drug-naïve) turning asymmetries that correlated exponentially with the depletion of DA biomarkers in the lesioned striata. These mice also exhibited a reduced capacity to remain on the accelerating rotarod. Oral administration of TC-8831, an NNR agonist with high specificity for ß2 subunits and a full agonist at producing DA release from striatal synaptosomes, attenuated unidirectional turning and improved motor coordination. In contrast, partial ß2 NNR agonist TC-8581 had no effect on behaviors in this model. This study demonstrates the potential of NNR targeting-compounds to facilitate motor function in PD.

Alpha7 nicotinic cholinergic neuromodulation may reconcile multiple neurotransmitter hypotheses of schizophrenia.

The long prevailing hypothesis of schizophrenia pathogenesis implicates dopaminergic systems in the mesolimbic pathways as responsible for the positive symptoms of schizophrenia (hallucinations and delusions) and those in the mesocortical pathway as contributing to the negative symptoms (e.g., social disconnection, flattened affect and anhedonia). Several challenges to the dopamine hypothesis and the proposal of an alternative hypothesis implicating glutamate have provided additional support for the development of non-dopaminergic drugs for the management of schizophrenia symptomatology. Furthermore, preclinical and clinical evidence of alpha7 neuronal nicotinic acetylcholine receptor-mediated benefits in the triad of positive symptoms, negative symptoms and cognitive dysfunction in schizophrenia, as well as the genetic linkage of this receptor to the disease, have added another level of complexity. Thus schizophrenia is increasingly believed to involve multi-neurotransmitter deficits, all of which may contribute to altered dopaminergic tone in the mesolimbic, mesocortical and other areas of the brain. In this paper we provide a model that reconciles the dopamine, glutamate and alpha7 cholinergic etiopathogenesis and is consistent with the clinical benefit derived from therapies targeted to these individual pathways.

Alpha7 neuronal nicotinic receptors as targets for novel therapies to treat multiple domains of schizophrenia.

A number of hypotheses have been put forth to explain the underlying abnormalities of schizophrenia. The widely held dopamine hypothesis suggests that positive symptoms are related to elevated subcortical dopamine transmission and that negative symptoms and cognitive impairments are associated with decreased cortical dopamine function. However, recent evidence suggests broader involvement of serotonergic, glutamatergic and other neurotransmitter systems and a growing body of evidence supports a role for nicotinic cholinergic systems. Based on post-mortem studies, there is a decreased density of neuronal nicotinic receptors (NNRs), especially the alpha7 NNR subtype, in the brains of schizophrenics. The alpha7 NNR subtype is the most abundant in the mammalian brain and has been shown to modulate multiple neuronal pathways that are compromised in schizophrenia, including dopaminergic, serotonergic, glutamatergic and GABAergic pathways. Familial linkage studies have associated regions of chromosome 15, which contains the alpha7 NNR gene, with schizophrenia and polymorphisms have been described in the promoter region of the alpha7 NNR gene. Observations from both animal and human studies that alpha7 NNR agonists can improve positive and negative symptoms as well as cognition to varying degrees further support the involvement of this receptor subtype in multiple deficits of schizophrenia and suggest that it may be feasible to develop novel therapies targeting alpha7 NNRs to treat all domains of the disease.