Age-related differences in affective behaviors in mice: possible role of prefrontal cortical-hippocampal functional connectivity and metabolomic profiles.

Introduction: The differential expression of emotional reactivity from early to late adulthood may involve maturation of prefrontal cortical responses to negative valence stimuli. In mice, age-related changes in affective behaviors have been reported, but the functional neural circuitry warrants further investigation. Methods: We assessed age variations in affective behaviors and functional connectivity in male and female C57BL6/J mice. Mice aged 10, 30 and 60 weeks (wo) were tested over 8 weeks for open field activity, sucrose preference, social interactions, fear conditioning, and functional neuroimaging. Prefrontal cortical and hippocampal tissues were excised for metabolomics. Results: Our results indicate that young and old mice differ significantly in affective behavioral, functional connectome and prefrontal cortical-hippocampal metabolome. Young mice show a greater responsivity to novel environmental and social stimuli compared to older mice. Conversely, late middle-aged mice (60wo group) display variable patterns of fear conditioning and during re-testing in a modified context. Functional connectivity between a temporal cortical/auditory cortex network and subregions of the anterior cingulate cortex and ventral hippocampus, and a greater network modularity and assortative mixing of nodes was stronger in young versus older adult mice. Metabolome analyses identified differences in several essential amino acids between 10wo mice and the other age groups. Discussion: The results support differential expression of 'emotionality' across distinct stages of the mouse lifespan involving greater prefrontal-hippocampal connectivity and neurochemistry.

Age-Related Differences in Affective Behaviors in Mice: Possible Role of Prefrontal Cortical-Hippocampal Functional Connectivity and Metabolomic Profiles.

The differential expression of emotional reactivity from early to late adulthood may involve maturation of prefrontal cortical responses to negative valence stimuli. In mice, age-related changes in affective behaviors have been reported, but the functional neural circuitry warrants further investigation. We assessed age variations in affective behaviors and functional connectivity in male and female C57BL6/J mice. Mice aged 10, 30 and 60 weeks (wo) were tested over 8 weeks for open field activity, sucrose preference, social interactions, fear conditioning, and functional neuroimaging. Prefrontal cortical and hippocampal tissues were excised for metabolomics. Our results indicate that young and old mice differ significantly in affective behavioral, functional connectome and prefrontal cortical-hippocampal metabolome. Young mice show a greater responsivity to novel environmental and social stimuli compared to older mice. Conversely, late middle-aged mice (60wo group) display variable patterns of fear conditioning and with re-testing with a modified context. Functional connectivity between a temporal cortical/auditory cortex network and subregions of the anterior cingulate cortex and ventral hippocampus, and a greater network modularity and assortative mixing of nodes was stronger in young versus older adult mice. Metabolome analyses identified differences in several essential amino acids between 10wo mice and the other age groups. The results support differential expression of 'emotionality' across distinct stages of the mouse lifespan involving greater prefrontal-hippocampal connectivity and neurochemistry.

Fixed Time-Point Analysis Reveals Repetitive Mild Traumatic Brain Injury Effects on Resting State Functional Magnetic Resonance Imaging Connectivity and Neuro-Spatial Protein Profiles.

Repetitive mild traumatic brain injuries (rmTBIs) are serious trauma events responsible for the development of numerous neurodegenerative disorders. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps of the molecular mechanisms responsible for neurodegeneration. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. Using the Closed-Head Impact Model of Engineered Rotational Acceleration, or CHIMERA, we measured neural changes following injury, including brain volume, diffusion tensor imaging, and resting-state functional magnetic resonance imaging coupled with graph theory and functional connectivity analyses. We determined the effect of rmTBI on markers of gliosis and used NanoString-GeoMx to add a digital-spatial protein profiling analysis of neurodegenerative disease-associated proteins in gray and white matter regions. Our analyses revealed aberrant connectivity changes in the thalamus, independent of microstructural damage or neuroinflammation. We also identified distinct changes in the levels of proteins linked to various neurodegenerative processes including total and phospho-tau species and cell proliferation markers. Together, our data show that rmTBI significantly alters brain functional connectivity and causes distinct protein changes in morphologically intact brain areas.

Compensatory functional connectome changes in a rat model of traumatic brain injury.

Penetrating cortical impact injuries alter neuronal communication beyond the injury epicentre, across regions involved in affective, sensorimotor and cognitive processing. Understanding how traumatic brain injury reorganizes local and brain wide nodal interactions may provide valuable quantitative parameters for monitoring pathological progression and recovery. To this end, we investigated spontaneous fluctuations in the functional MRI signal obtained at 11.1 T in rats sustaining controlled cortical impact and imaged at 2- and 30-days post-injury. Graph theory-based calculations were applied to weighted undirected matrices constructed from 12 879 pairwise correlations between functional MRI signals from 162 regions. Our data indicate that on Days 2 and 30 post-controlled cortical impact there is a significant increase in connectivity strength in nodes located in contralesional cortical, thalamic and basal forebrain areas. Rats imaged on Day 2 post-injury had significantly greater network modularity than controls, with influential nodes (with high eigenvector centrality) contained within the contralesional module and participating less in cross-modular interactions. By Day 30, modularity and cross-modular interactions recover, although a cluster of nodes with low strength and low eigenvector centrality remain in the ipsilateral cortex. Our results suggest that changes in node strength, modularity, eigenvector centrality and participation coefficient track early and late traumatic brain injury effects on brain functional connectivity. We propose that the observed compensatory functional connectivity reorganization in response to controlled cortical impact may be unfavourable to brain wide communication in the early post-injury period.

Contextual experience modifies functional connectome indices of topological strength and efficiency.

Stimuli presented at short temporal delays before functional magnetic resonance imaging (fMRI) can have a robust impact on the organization of synchronous activity in resting state networks. This presents an opportunity to investigate how sensory, affective and cognitive stimuli alter functional connectivity in rodent models. In the present study we assessed the effect on functional connectivity of a familiar contextual stimulus presented 10 min prior to sedation for imaging. A subset of animals were co-presented with an unfamiliar social stimulus in the same environment to further investigate the effect of familiarity on network topology. Rats were imaged at 11.1 T and graph theory analysis was applied to matrices generated from seed-based functional connectivity data sets with 144 brain regions (nodes) and 10,152 pairwise correlations (after excluding 144 diagonal edges). Our results show substantial changes in network topology in response to the familiar (context). Presentation of the familiar context, both in the absence and presence of the social stimulus, strongly reduced network strength, global efficiency, and altered the location of the highest eigenvector centrality nodes from cortex to the hypothalamus. We did not observe changes in modular organization, nodal cartographic assignments, assortative mixing, rich club organization, and network resilience. We propose that experiential factors, perhaps involving associative or episodic memory, can exert a dramatic effect on functional network strength and efficiency when presented at a short temporal delay before imaging.