Delayed formation of neural representations of space in aged mice.

Aging is associated with cognitive deficits, with spatial memory being very susceptible to decline. The hippocampal dentate gyrus (DG) is important for processing spatial information in the brain and is particularly vulnerable to aging, yet its sparse activity has led to difficulties in assessing changes in this area. Using in vivo two-photon calcium imaging, we compared DG neuronal activity and representations of space in young and aged mice walking on an unfamiliar treadmill. We found that calcium activity was significantly higher and less tuned to location in aged mice, resulting in decreased spatial information encoded in the DG. However, with repeated exposure to the same treadmill, both spatial tuning and information levels in aged mice became similar to young mice, while activity remained elevated. Our results show that spatial representations of novel environments are impaired in the aged hippocampus and gradually improve with increased familiarity. Moreover, while the aged DG is hyperexcitable, this does not disrupt neural representations of familiar environments.

Delayed formation of neural representations of space in aged mice.

Aging is associated with cognitive deficits, with spatial memory being very susceptible to decline. The hippocampal dentate gyrus (DG) is important for processing spatial information in the brain and is particularly vulnerable to aging, yet its sparse activity has led to difficulties in assessing changes in this area. Using in vivo two-photon calcium imaging, we compared DG neuronal activity and representations of space in young and aged mice walking on an unfamiliar treadmill. We found that calcium activity was significantly higher and less tuned to location in aged mice, resulting in decreased spatial information encoded in the DG. However, with repeated exposure to the same treadmill, both spatial tuning and information levels in aged mice became similar to young mice, while activity remained elevated. Our results show that spatial representations of novel environments are impaired in the aged hippocampus and gradually improve with increased familiarity. Moreover, while the aged DG is hyperexcitable, this does not disrupt neural representations of familiar environments.

Retrosplenial cortex microglia and perineuronal net densities are associated with memory impairment in aged rhesus macaques.

Synapse loss and altered plasticity are significant contributors to memory loss in aged individuals. Microglia, the innate immune cells of the brain, play critical roles in maintaining synapse function, including through a recently identified role in regulating the brain extracellular matrix. This study sought to determine the relationship between age, microglia, and extracellular matrix structure densities in the macaque retrosplenial cortex. Twenty-nine macaques ranging in age from young adult to aged were behaviorally characterized on 3 distinct memory tasks. Microglia, parvalbumin (PV)-expressing interneurons and extracellular matrix structures, known as perineuronal nets (PNNs), were immuno- and histochemically labeled. Our results indicate that microglia densities increase in the retrosplenial cortex of aged monkeys, while the proportion of PV neurons surrounded by PNNs decreases. Aged monkeys with more microglia had fewer PNN-associated PV neurons and displayed slower learning and poorer performance on an object recognition task. Stepwise regression models using age and the total density of aggrecan, a chondroitin sulfate proteoglycan of PNNs, better predicted memory performance than did age alone. Together, these findings indicate that elevated microglial activity in aged brains negatively impacts cognition in part through mechanisms that alter PNN assembly in memory-associated brain regions.

Transcriptional regulation of neural stem cell expansion in the adult hippocampus.

Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors (TFs) in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of TFs regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show in mice that the TF Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital two-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a molecular blueprint for RGL symmetric self-renewal that was characterized by upregulation of genetic programs underlying Notch and mitogen signaling, cell cycle, fatty acid oxidation, and lipogenesis. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.

In humans and other mammals, a region of the brain known as the hippocampus plays important roles in memory. New experiences guide cells in the hippocampus known as radial-glial neural stem cells (RGLs) to divide to make new neurons and other types of cells involved in forming memories. Each time an RGL divides, it can choose to divide asymmetrically to maintain a copy of itself and make a new cell of another type, or divide symmetrically (a process known as symmetric self-renewal) to produce two RGLs. Symmetric self-renewal helps to restore and replenish the pool of stem cells in the hippocampus that are lost due to injury or age, allowing us to continue making new neurons. Proteins known as transcription factors are believed to control how RGLs divide. Previous studies have identified several transcription factors that regulate the RGLs splitting asymmetrically to make neurons and other cells. But the identities of the transcription factors that regulate symmetric self-renewal in the adult hippocampus have remained elusive. Here, Guo et al. searched for transcription factors that regulate symmetric self-renewal of RGLs in mice. The experiments found that RGLs that are resting and not dividing (referred to as 'quiescent') have higher levels of a transcription factor called Klf9 than RGLs that are actively dividing. Loss of the gene encoding Klf9 triggered quiescent RGLs to start dividing, and further experiments showed that Klf9 directly inhibited symmetric self-renewal. Guo et al. then used an approach called in vivo translational profiling to generate a blueprint that revealed new insights into the molecular processes involved in this symmetric division. These findings pave the way for researchers to develop strategies that may expand the numbers of stem cells in the hippocampus. This could eventually be used to help replenish brain circuits with neurons and improve the memory of individuals with Alzheimer's disease or other conditions that cause memory loss.

Donor-derived vasculature is required to support neocortical cell grafts after stroke.

Neural precursor cells (NPCs) transplanted into the adult neocortex generate neurons that synaptically integrate with host neurons, supporting the possibility of achieving functional tissue repair. However, poor survival and functional neuronal recovery of transplanted NPCs greatly limits engraftment. Here, we test the hypothesis that combining blood vessel-forming vascular cells with neuronal precursors improves engraftment. By transplanting mixed embryonic neocortical cells into adult mice with neocortical strokes, we show that transplant-derived neurons synapse with appropriate targets while donor vascular cells form vessels that fuse with the host vasculature to perfuse blood within the graft. Although all grafts became vascularized, larger grafts had greater contributions of donor-derived vessels that increased as a function of their distance from the host-graft border. Moreover, excluding vascular cells from the donor cell population strictly limited graft size. Thus, inclusion of vessel-forming vascular cells with NPCs is required for more efficient engraftment and ultimately for tissue repair.

Treadmill-based task for assessing spatial memory in head-fixed mice.

Several mouse in vivo neuronal recording techniques require head fixation. Head-fixed treadmill walking can be used to design tasks that enable the study of neural activity in the context of behavior. Here, we provide a detailed protocol for constructing a treadmill with tactile spatial cues, training mice on a rewarded behavioral task, and analyzing behavioral data. We discuss common problems and solutions we have developed to optimize training. Finally, we demonstrate how to test spatial memory performance using this task.

Attitudes Toward Computers Moderate the Effect of Computerized Cognitive Trainings in Oldest-Old Senior Living Center Residents.

BACKGROUND AND OBJECTIVES: Computerized cognitive interventions (CCIs) have been increasingly implemented among older adults with mild cognitive impairment (MCI). However, older individuals' attitudes toward technology may limit CCI engagement. This exploratory-developmental study examined whether a "multi-functional interactive computer system" (MICS), which provides pleasurable activities via computer, would improve attitudes toward computers and in turn increase the efficacy of a subsequent CCI. RESEARCH DESIGN AND METHODS: A phase one double-blind trial randomized 49 seniors with MCI to a MICS + CCI condition or a CCI-only condition. Attitudes toward technology use was assessed using The Attitudes Toward Computers Questionnaire (ATCQ), and cognition was assessed using episodic memory and executive function composite scores at baseline, the ends of MICS and CCI phases, and 3-month follow-up. RESULTS: The MICS + CCI group did not show significantly greater improvement in cognition than the CCI only group. Secondary analyses indicated that improvement in executive function from baseline occurred in both groups. Participants who did show improved attitudes toward computers, whether through MICS or simply computer exposure itself, showed improvement in executive function. DISCUSSION AND IMPLICATION: Participants in the MICS + CCI group used MICS less than expected. A more structured and supervised approach may be needed to facilitate MICS exposure. Improved attitudes toward computers regardless of MICS exposure may benefit candidates for CCI.

Decoding individual identity from brain activity elicited in imagining common experiences.

Everyone experiences common events differently. This leads to personal memories that presumably provide neural signatures of individual identity when events are reimagined. We present initial evidence that these signatures can be read from brain activity. To do this, we progress beyond previous work that has deployed generic group-level computational semantic models to distinguish between neural representations of different events, but not revealed interpersonal differences in event representations. We scanned 26 participants' brain activity using functional Magnetic Resonance Imaging as they vividly imagined themselves personally experiencing 20 common scenarios (e.g., dancing, shopping, wedding). Rather than adopting a one-size-fits-all approach to generically model scenarios, we constructed personal models from participants' verbal descriptions and self-ratings of sensory/motor/cognitive/spatiotemporal and emotional characteristics of the imagined experiences. We demonstrate that participants' neural representations are better predicted by their own models than other peoples'. This showcases how neuroimaging and personalized models can quantify individual-differences in imagined experiences.

Brain structural connectomes indicate shared neural circuitry involved in subjective experience of cognitive and physical fatigue in older adults.

Cumulative evidence suggests the existence of common processes underlying subjective experience of cognitive and physical fatigue. However, mechanistic understanding of the brain structural connections underlying the experience of fatigue in general, without the influence of clinical conditions, is limited. The purpose of the study was to examine the relationship between structural connectivity and perceived state fatigue in older adults. We enrolled cognitively and physically healthy older individuals (n = 52) and categorized them into three groups (low cognitive/low physical fatigue; low cognitive/high physical fatigue; high cognitive/low physical fatigue; no subjects had high cognitive/high physical fatigue) based on perceived fatigue from cognitive and physical fatigue manipulation tasks. Using sophisticated diffusion tensor imaging processing techniques, we extracted connectome matrices for six different characteristics of whole-brain structural connections for each subject. Tensor network principal component analysis was used to examine group differences in these connectome matrices, and extract principal brain networks for each group. Connected surface area of principal brain networks differentiated the two high fatigue groups from the low cognitive/physical fatigue group (high vs. low physical fatigue, p = 0.046; high vs. low cognitive fatigue, p = 0.036). Greater connected surface area within striatal-frontal-parietal networks was correlated with lower cognitive and physical fatigue, and was predictive of perceived physical and cognitive fatigue measures not used for group categorization (Pittsburgh fatigability physical subscale, R2 = 0.70, p < 0.0001; difference in self-report fatigue before and after gambling tasks, R2 = 0.54, p < 0.0001). There are potentially structural connectomes resilient to both cognitive and physical fatigue in older adults.

The mediating role of hippocampal networks on stress regulation in amnestic mild cognitive impairment.

OBJECTIVES: To examine the role of the hippocampus in stress regulation in older adults with amnestic mild cognitive impairment (aMCI). METHODS: This study combined resting-state functional MRI, structural MRI, self-reported chronic stress exposure, and an electrocardiography-based acute stress protocol to compare aMCI group (n = 17) to their cognitively healthy counterparts (HC, n = 22). RESULTS: For the entire sample, there was a positive correlation between chronic stress exposure and acute stress regulation. The aMCI group showed significantly smaller volumes in the right hippocampus than HC. The two groups did not differ in chronic stress exposure or acute stress regulation. In the HC group, the left hippocampal connectivity with inferior parietal lobe was significantly correlated with both the chronic stress and acute stress. In the aMCI group, the left hippocampal connectivity with both the right insula and the left precentral gyrus was significantly correlated to chronic stress exposure and acute stress regulation. Additionally, the left hippocampal connectivity with right insula significantly mediated the relationship between chronic stress exposure and acute stress regulation in aMCI group. CONCLUSIONS: Extra hippocampal networks may be recruited as compensation to attend the maintenance of relatively normal stress regulation in aMCI by alleviating the detrimental effects of chronic stress exposure on acute stress regulation.

Cognitive fatigue and cortical-striatal network in old age.

Cognitive fatigue (CF) is among the most common and disturbing aging symptoms, and substantially interferes with activities demanding sustained mental effort. Here we examined the relationship between the cortical-striatal network and CF (assessed by the 18-item visual analogue scale) when a group of cognitively and physically healthy older adults participated in a 30-minute cognitively fatiguing task-related fMRI experiment. We also explored whether CF would interfere with the "Posterior-Anterior Shifting in Aging" (PASA) phenomenon, an aging-associated neural reliance on frontal regions to support cognitive capacity. We revealed that decreased connectivity strength of the cortical-striatal network over the course of the task was related to higher CF. Correlation between CF and the cortical-striatal network was more robust in anterior relative to posterior components. Moreover, a positive relationship between reliance on the anterior part of the cortical-striatal network and cognitive performance only existed among older adults experiencing low CF. These findings suggest a crucial role of the cortical-striatal network, especially the anterior component, in linking to CF. The PASA phenomenon may only be applicable to older adults without vulnerability to CF.

Transglutaminase-6 is an autoantigen in progressive multiple sclerosis and is upregulated in reactive astrocytes.

BACKGROUND: Transglutaminase-6 (TGM6), a member of the transglutaminase enzyme family, is found predominantly in central nervous system (CNS) neurons under physiological conditions. It has been proposed as an autoimmune target in cerebral palsy, gluten-sensitive cerebellar ataxia, and schizophrenia. OBJECTIVE: To investigate TGM6 involvement in multiple sclerosis (MS). METHODS: Antibody levels against TGM6 (TGM6-IgG) were measured in the cerebrospinal fluid (CSF) of 62 primary progressive multiple sclerosis (PPMS), 85 secondary progressive multiple sclerosis (SPMS), and 50 relapsing-remitting multiple sclerosis (RRMS) patients and 51 controls. TGM6 protein expression was analyzed in MS brain autopsy, murine experimental autoimmune encephalomyelitis (EAE), and cultured astrocytes. RESULTS: CSF levels of TGM6-IgG were significantly higher in PPMS and SPMS compared to RRMS and controls. Notably, patients with clinically active disease had the highest TGM6-IgG levels. Additionally, brain pathology revealed strong TGM6 expression by reactive astrocytes within MS plaques. In EAE, TGM6 expression in the spinal cord correlated with disease course and localized in reactive astrocytes infiltrating white matter lesions. Finally, knocking down TGM6 expression in cultured reactive astrocytes reduced their glial fibrillary acidic protein (GFAP) expression. CONCLUSION: TGM6-IgG may be a candidate CSF biomarker to predict and monitor disease activity in progressive MS patients. Furthermore, TGM6 expression by reactive astrocytes within both human and mouse lesions suggests its involvement in the mechanisms of glial scar formation.