Changes in memory performance are one of the hallmark symptoms of mild cognitive impairment and are affected by healthy aging as well. Pattern separation, which refers to the process of ...orthogonalizing overlapping inputs into distinct memory representations, may be a sensitive marker of these memory changes. Here, we describe a paradigm, the Behavioral Pattern Separation Task—Object Version (BPS-O task), which reveals age-related changes in pattern separation performance. Specifically, we report an age-related decline in pattern separation in healthy adults, ranging from ages 20 to 89. When we classify those individuals aged 60 and older into two groups, Aged Unimpaired (AU) and Aged Impaired (AI) based on their delayed word recall performance, we observe impairments in pattern separation performance in the Impaired group, but no overall impairment in recognition performance. In contrast, those individuals diagnosed with mild cognitive impairment demonstrate worse performance than age-matched controls in both pattern separation and recognition memory performance. Therefore, the BPS-O task provides a sensitive measure for observing changes in memory performance across the lifespan and may be useful for the early detection of memory impairments that may provide an early signal of later development to mild cognitive impairment.
► Behavioral pattern separation declines in human aging. ► MCI individuals exhibit impairments in both recognition memory and behavioral pattern separation. ► Aged Impaired adults demonstrate pattern separation deficits but normal recognition.
Converging data from rodents and humans have demonstrated an age-related decline in pattern separation abilities (the ability to discriminate among similar experiences). Several studies have proposed ...the dentate and CA3 subfields of the hippocampus as the potential locus of this change. Specifically, these studies identified rigidity in place cell remapping in similar environments in the CA3. We used high-resolution fMRI to examine activity profiles in the dentate gyrus and CA3 in young and older adults as stimulus similarity was incrementally varied. We report evidence for "representational rigidity" in older adults' dentate/CA3 that is linked to behavioral discrimination deficits. Using ultrahigh-resolution diffusion imaging, we quantified both the integrity of the perforant path as well as dentate/CA3 dendritic changes and found that both were correlated with dentate/CA3 functional rigidity. These results highlight structural and functional alterations in the hippocampal network that predict age-related changes in memory function and present potential targets for intervention.
Pattern separation, the process of transforming similar representations or memories into highly dissimilar, nonoverlapping representations, is a key component of many functions ascribed to the ...hippocampus. Computational models have stressed the role of the hippocampus and, in particular, the dentate gyrus and its projections into the CA3 subregion in pattern separation. We used high-resolution (1.5-millimeter isotropic voxels) functional magnetic resonance imaging to measure brain activity during incidental memory encoding. Although activity consistent with a bias toward pattern completion was observed in CA1, the subiculum, and the entorhinal and parahippocampal cortices, activity consistent with a strong bias toward pattern separation was observed in, and limited to, the CA3/dentate gyrus. These results provide compelling evidence of a key role of the human CA3/dentate gyrus in pattern separation.
Hippocampal circuit alterations that differentially affect hippocampal subfields are associated with age-related memory decline. Additionally, functional organization along the longitudinal axis of ...the hippocampus has revealed distinctions between anterior and posterior (A-P) connectivity. Here, we examined the functional connectivity (FC) differences between young and older adults at high-resolution within the medial temporal lobe network (entorhinal, perirhinal, and parahippocampal cortices), allowing us to explore how hippocampal subfield connectivity across the longitudinal axis of the hippocampus changes with age. Overall, we found reliably greater connectivity for younger adults than older adults between the hippocampus and parahippocampal cortex (PHC) and perirhinal cortex (PRC). This drop in functional connectivity was more pronounced in the anterior regions of the hippocampus than the posterior ones, consistent for each of the hippocampal subfields. Further, intra-hippocampal connectivity also reflected an age-related decrease in functional connectivity within the anterior hippocampus in older adults that was offset by an increase in posterior hippocampal functional connectivity. Interestingly, the anterior-posterior dysfunction in older adults between hippocampus and PHC was predictive of lure discrimination performance on the Mnemonic similarity task (MST), suggesting a role in memory performance. While age-related dysfunction within the hippocampal subfields has been well-documented, these results suggest that the age-related dysfunction in hippocampal connectivity across the longitudinal axis may also contribute significantly to memory decline in older adults.
Calorie restriction (CR) prevents many age-associated diseases and prolongs the lifespan. CR induces multiple metabolic and physiologic modifications, including anti-inflammatory, antioxidant, and ...neuroprotective effects that may be beneficial in multiple sclerosis (MS). The present studies sought to determine whether CR or increased calorie intake alters the course of experimental autoimmune encephalomyelitis (EAE), the leading animal model for MS. SJL and C57BL/6 mice were subjected to 40% CR beginning at 5 weeks of age. After 5 weeks of CR, EAE was induced by immunizing with proteolipid protein in SJL mice and with myelin oligodendrocyte glycoprotein in C57BL/6 mice. Clinical, histologic, and immunologic features of EAE were compared with mice fed ad libitum and to SJL mice fed a high-fat, high-calorie diet. CR ameliorated clinical EAE in both mouse strains with less severe inflammation, demyelination, and axon injury. No suppression of immune function was observed. A high-calorie diet did not alter the EAE course. CR was associated with increased plasma levels of corticosterone and adiponectin and reduced concentrations of IL-6 and leptin. The CR-induced hormonal, metabolic, and cytokine changes observed in our studies suggest a combined anti-inflammatory and neuroprotective effect. CR with adequate nutrition and careful medical monitoring should be explored as a potential treatment for MS.
22q11.2 microdeletions result in specific cognitive deficits and schizophrenia. Analysis of Df(16)A+/− mice, which model this microdeletion, revealed abnormalities in the formation of neuronal ...dendrites and spines, as well as altered brain microRNAs. Here, we show a drastic reduction of miR-185, which resides within the 22q11.2 locus, to levels more than expected by a hemizygous deletion, and we demonstrate that this reduction alters dendritic and spine development. miR-185 represses, through an evolutionarily conserved target site, a previously unknown inhibitor of these processes that resides in the Golgi apparatus and shows higher prenatal brain expression. Sustained derepression of this inhibitor after birth represents the most robust transcriptional disturbance in the brains of Df(16)A+/− mice and results in structural alterations in the hippocampus. Reduction of miR-185 also has milder age- and region-specific effects on the expression of some Golgi-related genes. Our findings illuminate the contribution of microRNAs in psychiatric disorders and cognitive dysfunction.
Display omitted
► A mouse model of a hemizygous 22q11.2 deletion shows over 50% reduction of miR-185 ► Mirta22 is a miR-185 target and a major effector of the 22q11.2 miRNA dysregulation ► Mirta22 is a prenatally biased neuronal inhibitor located in the Golgi apparatus ► Altered levels of miR-185 and Mirta22 affect dendrite and spine development
Hemizygous 22q11.2 microdeletions result in specific cognitive deficits and schizophrenia. Downregulation of a microRNA within this region, miR-185, results in postnatal derepression of a previously unknown inhibitor of neuronal maturation and impaired neuronal connections in the adult brain.
Abnormalities in functional connectivity between brain areas have been postulated as an important pathophysiological mechanism underlying schizophrenia. In particular, macroscopic measurements of ...brain activity in patients suggest that functional connectivity between the frontal and temporal lobes may be altered. However, it remains unclear whether such dysconnectivity relates to the aetiology of the illness, and how it is manifested in the activity of neural circuits. Because schizophrenia has a strong genetic component, animal models of genetic risk factors are likely to aid our understanding of the pathogenesis and pathophysiology of the disease. Here we study Df(16)A+/- mice, which model a microdeletion on human chromosome 22 (22q11.2) that constitutes one of the largest known genetic risk factors for schizophrenia. To examine functional connectivity in these mice, we measured the synchronization of neural activity between the hippocampus and the prefrontal cortex during the performance of a task requiring working memory, which is one of the cognitive functions disrupted in the disease. In wild-type mice, hippocampal-prefrontal synchrony increased during working memory performance, consistent with previous reports in rats. Df(16)A+/- mice, which are impaired in the acquisition of the task, showed drastically reduced synchrony, measured both by phase-locking of prefrontal cells to hippocampal theta oscillations and by coherence of prefrontal and hippocampal local field potentials. Furthermore, the magnitude of hippocampal-prefrontal coherence at the onset of training could be used to predict the time it took the Df(16)A+/- mice to learn the task and increased more slowly during task acquisition. These data suggest how the deficits in functional connectivity observed in patients with schizophrenia may be realized at the single-neuron level. Our findings further suggest that impaired long-range synchrony of neural activity is one consequence of the 22q11.2 deletion and may be a fundamental component of the pathophysiology underlying schizophrenia.
is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of
in a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking
(PS2APP;Trem2
) ...at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2
mice, with
-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2
females at 6-7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2
mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2
brains, and the Aβ42:Aβ40 ratio was elevated. The amount of soluble, fibrillar Aβ oligomers also increased in PS2APP;Trem2
hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2
mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2
mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of
deficiency than amyloid plaque load, suggesting that the microglial packing of Aβ into dense plaque is an important neuroprotective activity.
Genetic studies indicate that
gene mutations confer increased Alzheimer's disease (AD) risk. We studied the effects of
deletion in the PS2APP mouse AD model, in which overproduction of Aβ peptide leads to amyloid plaque formation and associated neuritic dystrophy. Interestingly, neuritic dystrophies were intensified in the brains of
-deficient mice, despite these mice displaying reduced plaque accumulation at later ages (12-22 months). Microglial clustering around plaques was impaired, plaques were more diffuse, and the Aβ42:Aβ40 ratio and amount of soluble, fibrillar Aβ oligomers were elevated in
-deficient brains. These results suggest that the Trem2-dependent compaction of Aβ into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic Aβ species.
The recent identification of highly superior autobiographical memory (HSAM) raised the possibility that there may be individuals who are immune to memory distortions. We measured HSAM participants’ ...and age- and sex-matched controls’ susceptibility to false memories using several research paradigms. HSAM participants and controls were both susceptible to false recognition of nonpresented critical lure words in an associative word-list task. In a misinformation task, HSAM participants showed higher overall false memory compared with that of controls for details in a photographic slideshow. HSAM participants were equally as likely as controls to mistakenly report they had seen nonexistent footage of a plane crash. Finding false memories in a superior-memory group suggests that malleable reconstructive mechanisms may be fundamental to episodic remembering. Paradoxically, HSAM individuals may retrieve abundant and accurate autobiographical memories using fallible reconstructive processes.
In the wake of the #BlackLivesMatter and #MeToo movements, police conduct has been increasingly scrutinized by the public, especially the use of excessive force, fatal shootings of unarmed civilians, ...and sexual harassment scandals within policing organizations. Through a review of the policing literature and data collected in a Canadian policing organization, we highlight how masculinity contest culture is related to police misconduct. All four masculinity contest culture dimensions can be observed in policing including: (1) “show no weakness,” (2) “strength and stamina,” (3) “put work first,” and (4) “dog‐eat‐dog.” Masculinity contest cultures lead to negative outcomes for both individual officers (e.g., harassment, discrimination, stress), policing organizations (e.g., lawsuits, turnover), and communities (e.g., officers’ use of excessive force). Training interventions are often suggested to prevent or remedy the negative effects of masculinity contest cultures in policing organizations. However, a review of the training literature suggests that training interventions are unlikely to be effective in contexts where organizational norms are at odds with the training content. Our analysis of police data, along with the literature review, conclude with a paradox—the very organizations that need training interventions the most (e.g., policing organizations that often promote and tolerate sexual harassment) are the least likely to benefit from those interventions. To address this paradox, we invoke the theory of social interactionism and reconceptualize training as an organizational sensegiving mechanism. This theoretical foundation offers new directions for future research on training in masculinity contest cultures and insights for practicing police administrators and public policy officials.
PDF
