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The role of non-cholinergic neurons in cholinergic neuromodulation.

During the last decades, the achievement of a better and improved quality of life has resulted in increased life expectancy. This is mainly due to progress in translational research and development of new therapeutic approaches. The downside is that age is one of the major risk factors for dementias and neurodegenerative disorders such as Alzheimer's disease (AD), characterized by a marked decline of cognitive functions (e.g. short- and long-term memory loss) and dysregulation of higher cortical functions (e.g. impaired judgement and thinking). The pathological condition of these diseases is disabling enough to compromise the activity of everyday life. Lengthening the life span has little value if the quality of life cannot be ensured. Unfortunately, the pathogenesis of AD is still far from being understood and this could be the reason why none of the currently available pharmacological therapies for this disease are satisfactory. Current treatments are purely symptomatic and do not act on the onset and progression of the pathology. It is well known that Basal Forebrain (BF) cholinergic neurons are prone to degeneration during aging as well as in dementias like AD. Furthermore, "the cholinergic hypothesis of geriatric cognitive dysfunction" is also supported by the significant correlation between the level of cholinergic depletion and the degree of cognitive deficits. Acetylcholine is a neuromodulator broadly investigated for its role in learning and memory, but it is not the only player in AD. In fact, in the BF, intermingled with cholinergic neurons, there are also two non-cholinergic neuronal types: GABAergic and glutamatergic neurons. It has been discovered that dysfunctions at the level of glutamatergic and GABAergic systems are involved as well in AD. Until recently, neuroscientists have limited the research of AD to the study of a single neuronal type (mainly BF cholinergic neurons), overlooking the possible role of non-cholinergic neuronal populations (GABAergic and glutamatergic). However, it is of the utmost importance to uncover the interaction between BF cholinergic and non-cholinergic neurons to develop novel strategies for the treatment of AD. The proposed research project aims to investigate the interaction between the three distinct BF populations and to elucidate how the BF cholinergic neuronal activity influences the other two BF neuronal types both in healthy and in pathological conditions. To date, it is still far from being understood how the neural state of the cholinergic neurons influences the GABAergic and glutamatergic neurons in the BF and how these, in turn, adjust cholinergic neuromodulation. We suggest to study the activity of BF neuronal populations and their interactions during spontaneous activity and determine the relationship of the activity of these three neuronal populations with whole brain functional connectivity. Then we will target and stimulate the BF cholinergic neurons using optogenetics to understand how it influences network interactions and to identify the optimal conditions of stimulation in an AD animal model that can induce network states as observed during spontaneous activity in healthy animals. To achieve these goals, we propose a methodological approach that is both innovative and multimodal because it combines cutting edge techniques such as fMRI tools, optogenetics and fiber-optic calcium recording. The results of this study will provide an increased and better understanding of BF neural circuitry, thus opening new future perspectives for the treatment of cognitive disorders.
Date:1 Oct 2018  →  31 Oct 2019
Disciplines:Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing
Project type:Collaboration project