title: Behavioural state differentially engages septohippocampal cholinergic and GABAergic neurons in R6/1 Huntington's disease mice.
abstract: Huntington's disease (HD) is a neurodegenerative condition characterised by progressive motor, psychological and cognitive decline. R6/1 HD transgenic mice model the clinical hippocampal-dependent cognitive deficits observed in patients. Cholinergic and GABAergic septohippocampal projections play important roles in hippocampal-dependent cognition. The current study examined neuronal activity of cholinergic and GABAergic septohippocampal projections in response to arousal elicited during differing behavioural states. The different behavioural states examined were; home cage (controls), acute exploration of a novel enriched environment and either spontaneous wakefulness (dark phase) or spontaneous sleep (light phase). We employed triple-label immunohistochemistry using c-Fos as an indirect marker of neuron activation and parvalbumin and choline acetyltransferase (ChAT) to label GABAergic and cholinergic neurons in the basal forebrain, respectively. The Y-maze was used to assess short-term hippocampal-dependent memory independently during either the dark or light phase and revealed a memory deficit in R6/1 HD mice compared to wild types that was particularly prominent during the dark phase. Three-way ANOVA of basal forebrain cholinergic and GABAergic activity through co-expression of c-Fos revealed overt responses to differing behavioural states. Both genotypes increased cholinergic neuron activity in response to exploring a novel enriched environment and also an increase during the dark phase compared to the light phase. Novel enriched environment exploration caused a larger response of GABAergic neuron activity in R6/1 HD mice, which also failed to increase the activity of GABAergic neurons during the dark phase compared to the light phase as observed for wildtype mice. Basal levels of c-Fos-positive cells were greatly increased in the hippocampal granule cell layer of R6/1 HD mice during both circadian phases. The differential activation of septohippocampal cholinergic and GABAergic neurons in R6/1 HD mice in response to differing behavioural states may be associated with impaired hippocampal-dependent short-term memory.
authors.affiliation: Florey Neuroscience Institutes, Melbourne Brain Centre, The University of Melbourne, Victoria 3010, Australia. mark.ransome@florey.edu.au
authors.forename: Mark I
authors.initials: MI
authors.lastname: Ransome
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hannan
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D059329:Cholinergic Neurons / Q000378:metabolism*; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D004777:Environment; D005106:Exploratory Behavior / Q000502:physiology; D059330:GABAergic Neurons / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology