Age-Dependent Degradation of Locomotion Encoding in Huntington’s Disease R6/2 Model Mice

Background: Huntington’s disease (HD) is an inherited fatal neurodegenerative disease, leading to neocortical and striatal atrophy. The commonly studied R6/2 HD transgenic mouse model displays progressive motor and cognitive deficits in parallel to major pathological changes in corticostriatal circuitry. Objective: To study how disease progression influences striatal encoding of movement. Methods: We chronically recorded neuronal activity in the dorsal striatum of R6/2 transgenic (Tg) mice and their age-matched nontransgenic littermate controls (WTs) during novel environment exposure, a paradigm which engages locomotion to explore the novel environment. Results: Exploratory locomotion degraded with age in Tg mice as compared to WTs. We encountered fewer putative medium spiny neurons (MSNs)—striatal projection neurons, and more inhibitory interneurons—putative fast spiking interneurons (FSIs) in Tg mice as compared to WTs. MSNs from Tg mice fired less spikes in bursts without changing their firing rate, while FSIs from these mice had a lower firing rate and more of them were task-responsive as compared to WTs. Additionally, MSNs from Tg mice displayed a reduced ability to encode locomotion across age groups, likely associated with their low prevalence in Tg mice, whereas the encoding of locomotion by FSIs from Tg mice was substantially reduced solely in old Tg mice as compared to WTs. Conclusion: Our findings reveal an age-dependent decay in striatal information processing in transgenic mice. We propose that the ability of FSIs to compensate for the loss of MSNs by processes of recruitment and enhanced task-responsiveness diminishes with disease progression, possibly manifested in the displayed age-dependent degradation of exploratory locomotion.

Inhibition of Orexin/Hypocretin Neurons Ameliorates Elevated Physical Activity and Energy Expenditure in the A53T Mouse Model of Parkinson’s Disease

Aside from the classical motor symptoms, Parkinson’s disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson’s. In this study, we hypothesized that Parkinson’s-disease-associated pathology affects orexin neurons and therefore impairs functions they regulate. To test this, we used a transgenic animal model of Parkinson’s, the A53T mouse. We measured body composition, exploratory locomotion, spontaneous physical activity, and energy expenditure. Further, we assessed alpha-synuclein accumulation, inflammation, and astrogliosis. Finally, we hypothesized that chemogenetic inhibition of orexin neurons would ameliorate observed impairments in the A53T mice. We showed that aging in A53T mice was accompanied by reductions in fat mass and increases in exploratory locomotion, spontaneous physical activity, and energy expenditure. We detected the presence of alpha-synuclein accumulations in orexin neurons, increased astrogliosis, and microglial activation. Moreover, loss of inhibitory pre-synaptic terminals and a reduced number of orexin cells were observed in A53T mice. As hypothesized, this chemogenetic intervention mitigated the behavioral disturbances induced by Parkinson’s disease pathology. This study implicates the involvement of orexin in early Parkinson’s-disease-associated impairment of hypothalamic-regulated physiological functions and highlights the importance of orexin neurons in Parkinson’s disease symptomology.

Exploratory locomotion, a predictor of addiction vulnerability, is oligogenic in rats selected for this phenotype

Artificially selected model organisms can reveal hidden features of the genetic architecture of the complex disorders that they model. Addictions are disease phenotypes caused by different intermediate phenotypes and pathways and thereby are potentially highly polygenic. High responder (bHR) and low responder (bLR) rat lines have been selectively bred (b) for exploratory locomotion (EL), a behavioral phenotype correlated with novelty-seeking, impulsive response to reward, and vulnerability to addiction, and is inversely correlated with spontaneous anxiety and depression-like behaviors. The rapid response to selection indicates loci of large effect for EL. Using exome sequencing of HR and LR rats, we identified alleles in gene-coding regions that segregate between the two lines. Quantitative trait locus (QTL) analysis in F2 rats derived from a bHR × bLR intercross confirmed that these regions harbored genes affecting EL. The combined effects of the seven genome-wide significant QTLs accounted for approximately one-third of the total variance in EL, and two-thirds of the variance attributable to genetic factors, consistent with an oligogenic architecture of EL estimated both from the phenotypic distribution of F2 animals and rapid response to selection. Genetic association in humans linkedAPBA2, the ortholog of the gene at the center of the strongest QTL, with substance use disorders and related behavioral phenotypes. Our finding is also convergent with molecular and animal behavioral studies implicating Apba2 in locomotion. These results provide multilevel evidence for genes/loci influencing EL. They shed light on the genetic architecture of oligogenicity in animals artificially selected for a phenotype modeling a more complex disorder in humans.

Effects of Anodal Transcranial Direct Current Stimulation (tDCS) Preconditioning Combined with Arachydonilcyclopropylamide (ACPA) on Exploratory Locomotion in Male Mice

Background: When confronting with an unfamiliar environment, animals exert orderly and complex behaviors called exploration. Locomotion is the most important part of exploratory behavior, but the principles of this behavior have not been fully understood yet. Here we studied the effects of the frontal region preconditioning with right and left frontal anodal transcranial direct current stimulation (tDCS) combined with the cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA) on locomotion in NMRI male mice. Materials and Methods: This study was carried out with 12 groups of NMRI mice (each group consisted of 8 mice), which were divided into 3 categories of ACPA alone, right, and left frontal anodal tDCS combined with ACPA. Anodal tDCS (with a current intensity of 0.2 mA for 20 minutes) was performed one day prior to ACPA intraperitoneal injection (0.01,0.05,0.1 mg/kg) and 15 minutes after injection the exploratory locomotion test was carried out. Results: The data showed that right frontal anodal tDCS combined with 0.01 and 0.05 mg/kg of ACPA and left frontal anodal tDCS combined with 0.05 mg/kg ACPA increased exploratory locomotion. Conclusions: Our finding suggested that combined implementation of right and left anodal tDCS and ACPA exerted anxiolytic properties and could increase exploratory related locomotion.[GMJ. 2016;5(4):173-79]