Abstract
Historically, many investigations into neurodegenerative diseases have focused on alterations in specific neuronal populations such as, for example, the loss of midbrain dopaminergic neurons in Parkinson’s disease (PD) and loss of cholinergic transmission in Alzheimer’s disease (AD). However, it has become increasingly clear that mammalian brain activities, from executive and motor functioning to memory and emotional responses, are strictly regulated by the integrity of multiple interdependent neuronal circuits. Among subcortical structures, the dopaminergic nigrostriatal and mesolimbic pathways as well as cholinergic innervation from basal forebrain and brainstem, play pivotal roles in orchestrating cognitive and non-cognitive symptoms in PD and AD. Understanding the functional interactions of these circuits and the consequent neurological changes that occur during degeneration provides new opportunities to understand the fundamental inter-workings of the human brain as well as develop new potential treatments for patients with dysfunctional neuronal circuits. Here, excerpted from a session of the European Behavioral Pharmacology Society meeting (Braga, Portugal, August 2019), we provide an update on our recent work in behavioral and cellular neuroscience that primarily focuses on interactions between cholinergic and dopaminergic systems in PD models, as well as stress in AD. These brief discussions include descriptions of (1) striatal cholinergic interneurons (CINs) and PD, (2) dopaminergic and cholinergic modulation of impulse control, and (3) the use of an implantable cell-based system for drug delivery directly the into brain and (4) the mechanisms through which day life stress, a risk factor for AD, damage protein and RNA homeostasis leading to AD neuronal malfunction.
Highlights
Research in neurodegenerative disorders have been focusing for many years on individual neuronal circuits and neurotransmitter systems [e.g., dopaminergic one in Parkinson’s disease (PD) and cholinergic in Alzheimer’s disease (AD)], it is increasingly accepted that different neurotransmitter systems are interrelated and affected under neurodegenerative conditions leading to deficits in related brain functions.For instance, while PD research is commonly focused on the motor deficits resulting from the loss of nigrostriatal dopaminergic neurons (Paolone et al, 2015), a majority of PD patients suffer from non-motor symptoms such as cognitive and emotional disorders (Chaudhuri et al, 2006)
cholinergic interneurons (CINs) photoinhibition of transgenic mice expressing encoding channelrhodopsin (ChR2) or halorhodopsin (eNpHR) in cholinergic neurons with similar partial 6-OHDA lesions alleviated the social recognition and cognitive deficits and reduced anxiety level, but did not affected the behavior of non-lesioned animals. These results suggest that even with a moderate striatal DA depletion, CINs reactivity may account for the cognitive and emotional symptoms measured in lesioned mice
Attentional performance is enhanced by the stimulation of the mesolimbic circuitry, the shell of the nucleus accumbens (NAc) through the activation of basal forebrain corticoperal projections (St Peters et al, 2011; Paolone et al, 2012, 2013). Given that these results support the potential use of encapsulated trophic factor-secreting cells in human diseases such as PD, AD and epilepsy, future studies might focus on the simultaneous delivery of multiple factors to more fully treat the pathology mosaicism that occurs in multisystem disorders such as neurological diseases
Summary
Research in neurodegenerative disorders have been focusing for many years on individual neuronal circuits and neurotransmitter systems [e.g., dopaminergic one in Parkinson’s disease (PD) and cholinergic in Alzheimer’s disease (AD)], it is increasingly accepted that different neurotransmitter systems are interrelated and affected under neurodegenerative conditions leading to deficits in related brain functions. CINs photoinhibition of transgenic mice expressing eNpHR in cholinergic neurons with similar partial 6-OHDA lesions alleviated the social recognition and cognitive deficits and reduced anxiety level, but did not affected the behavior of non-lesioned animals These results suggest that even with a moderate striatal DA depletion, CINs reactivity may account for the cognitive and emotional symptoms measured in lesioned mice. Reducing their activity locally in the striatum may appear to be an alternative therapeutic target to reduce non-motor symptoms early in the disease in addition to alleviate motor impairments in the late-stage of PD (Ztaou et al, 2018; Ztaou and Amalric, 2019). Optogenetic modulation of striatal CINs may provide new tools to treat both motor and cognitive symptoms of Parkinsonian patients
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