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Activation of glucose-sensing neurons in the ventromedial hypothalamic nucleus using radio waves or magnetic fields remotely and non-invasively in vivo increases plasma glucose and glucagon, and suppresses plasma insulin; conversely, remote inhibition of glucose-sensing neurons decreased blood glucose and increased plasma insulin. Remote control of animal behaviour This study describes a new technology that allows neurons to be activated or inhibited remotely in freely moving animals using radio waves or magnetic fields. Jeffrey Friedman and colleagues used an iron-binding protein tethered to a heat-sensitive protein to excite or inhibit neurons in the ventromedial hypothalamic nucleus in mice. Activation of glucose-sensing neurons increased plasma glucose and glucagon, suppressed plasma insulin and increased feeding. Inhibition decreased blood glucose, increased plasma insulin and suppressed the response to hypoglycaemia. As well as enabling remote control of cellular activity in basic research, this approach has potential therapeutic implications as a minimally invasive alternative to deep brain stimulation. Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP–TRPV1) 1 . Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase–Cre mice, which express Cre in glucose-sensing neurons 2 . Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types.

In the present study, we examined the relationship between developmental modulation of socioaffective brain systems and adolescents' preoccupation with social evaluation. Child, adolescent, and adult participants viewed cues indicating that a camera was alternately off, warming up, or projecting their image to a peer during the acquisition of behavioral-, autonomic-, and neural-response (functional MRI) data. Believing that a peer was actively watching them was sufficient to induce self-conscious emotion that rose in magnitude from childhood to adolescence and partially subsided into adulthood. Autonomic arousal was uniquely heightened in adolescents. These behavioral patterns were paralleled by emergent engagement of the medial prefrontal cortex (MPFC) and striatum-MPFC connectivity during adolescence, which are thought to promote motivated social behavior in adolescence. These findings demonstrate that adolescents' self-consciousness is related to age-dependent sensitivity of brain systems critical to socioaffective processes. Further, unique interactions between the MPFC and striatum may provide a mechanism by which social-evaluation contexts influence adolescent behavior.

Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer’s disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31 Phosphorus Magnetic Resonance Spectroscopy ( 31 P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40–65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4+ men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men’s brains to a similar metabolic range as women’s brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD.

Ovarian hormones, particularly 17β-estradiol, are involved in numerous neurophysiological and neurochemical processes, including those subserving cognitive function. Estradiol plays a key role in the neurobiology of aging, in part due to extensive interconnectivity of the neural and endocrine system. This aspect of aging is fundamental for women’s brains as all women experience a drop in circulating estradiol levels in midlife, after menopause. Given the importance of estradiol for brain function, it is not surprising that up to 80% of peri-menopausal and post-menopausal women report neurological symptoms including changes in thermoregulation (vasomotor symptoms), mood, sleep, and cognitive performance. Preclinical evidence for neuroprotective effects of 17β-estradiol also indicate associations between menopause, cognitive aging, and Alzheimer’s disease (AD), the most common cause of dementia affecting nearly twice more women than men. Brain imaging studies demonstrated that middle-aged women exhibit increased indicators of AD endophenotype as compared to men of the same age, with onset in perimenopause. Herein, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining cognition in women, with evidence implicating menopause-related declines in 17β-estradiol in cognitive aging and AD risk. We will review research focused on the role of endogenous and exogenous estrogen exposure as a key underlying mechanism to neuropathological aging in women, with a focus on whether brain structure, function and neurochemistry respond to hormone treatment. While still in development, this research area offers a new sex-based perspective on brain aging and risk of AD, while also highlighting an urgent need for better integration between neurology, psychiatry, and women’s health practices.

17β-estradiol, the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo brain 18 F-fluoroestradiol ( 18 F-FES) Positron Emission Tomography (PET) study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age, plasma estradiol and sex hormone binding globulin, and were highly consistent, correctly classifying all women as being postmenopausal or premenopausal. Higher ER density in target regions was associated with poorer memory performance for both postmenopausal and perimenopausal groups, and predicted presence of self-reported mood and cognitive symptoms after menopause. These findings provide novel insights on brain ER density modulation by female neuroendocrine aging, with clinical implications for women’s health.

Testosterone, an essential sex steroid hormone, influences brain health by impacting neurophysiology and neuropathology throughout the lifespan in both genders. However, human research in this area is limited, particularly in women. This study examines the associations between testosterone levels, gray matter volume (GMV) and cerebral blood flow (CBF) in midlife individuals at risk for Alzheimer’s disease (AD), according to sex and menopausal status. A cohort of 294 cognitively normal midlife participants, 83% female, ages 35–65 years, with an AD family history and/or Apolipoprotein E epsilon 4 (APOE-4) genotype, underwent volumetric Magnetic Resonance Imaging (MRI) to measure GMV and MR-Arterial Spin Labeling (ASL) for measurement of CBF. We used voxel-based analysis and volumes of interest to test for associations between testosterone (both total and free testosterone) and brain imaging outcomes, stratified by sex and menopausal status. Higher total and free testosterone levels were associated with larger GMV in men, with peak effects in frontal and temporal regions. Conversely, in women, higher testosterone levels correlated with higher CBF, with peak effects in frontal and limbic regions, subcortical areas and hypothalamus. Among women, associations between testosterone and GMV were observed at the premenopausal and perimenopausal stages, but not postmenopause, whereas associations of testosterone with CBF were significant starting at the perimenopausal stage and were more pronounced among hormone therapy non-users. Results were independent of age, APOE-4 status, midlife health indicators, and sex hormone-binding globulin levels. These findings indicate sex-specific neurophysiological effects of testosterone in AD-vulnerable regions in midlife individuals at risk for AD, with variations observed across sex and menopausal status. This underscores the need for further research focusing on the neuroprotective potential of testosterone in both sexes.

Women are at greater lifetime risk for Alzheimer’s disease (AD), potentially due to midlife endocrine transition effects on bioenergetics and gray and white matter volumes. Key to effective neurotransmission is white matter integrity. In this cross-sectional diffusion-weighted imaging analysis, we investigated white matter micro- and macrostructure in 137 cognitively normal, midlife adults, including 34 premenopausal, 39 perimenopausal, 27 postmenopausal women, and 37 men. Compared to men, premenopausal and postmenopausal women exhibited greater fiber density and fiber density-cross-section (FDC) across most tracts as well as higher fractional anisotropy (FA) and lower mean diffusivity in the fornix and corpus callosum, indicating denser, more organized white matter. Perimenopausal women exhibited few differences in fiber cross-section and FDC and lower FA in the bilateral fornix, differing from what was observed in pre- and postmenopausal women. These cross-sectional results suggest menopause stage-dependent sex differences in white matter organization, coinciding with changes in estrogen availability. Importantly, the perimenopause emerges as a critical window of neural reorganization in the female midlife aging brain characterized by temporary convergence toward male-like white matter organization. Future longitudinal analyses are key to identifying women who do or do not revert to a premenopausal profile, which may inform AD risk.

Increasing evidence implicates sex and endocrine aging effects on brain bioenergetic aging in the greater lifetime risk of Alzheimer’s disease (AD) in women. We conducted 31 Phosphorus Magnetic Resonance Spectroscopy ( 31 P-MRS) to assess the impact of sex and menopause on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters/phosphodiesters (PME/PDE)] in 216 midlife cognitively normal individuals at risk for AD, 80% female. Ninety-seven participants completed amyloid-beta (Aβ) 11 C-PiB PET. Women exhibited higher ATP utilization than men in AD-vulnerable frontal, posterior cingulate, fusiform, medial and lateral temporal regions (p < 0.001). This profile was evident in frontal cortex at the pre-menopausal and peri-menopausal stage and extended to the other regions at the post-menopausal stage (p = 0.001). Results were significant after multi-variable adjustment for age, APOE-4 status, midlife health indicators, history of hysterectomy/oophorectomy, use of menopause hormonal therapy, and total intracranial volume. While associations between ATP/PCr and Aβ load were not significant, individuals with the highest Aβ load were post-menopausal and peri-menopausal women with ATP/PCr ratios in the higher end of the distribution. No differences in Pi/PCr, Pi/ATP or PME/PDE were detected. Outcomes are consistent with dynamic bioenergetic brain adaptations that are associated with female sex and endocrine aging.

Emerging evidence implicates chronic psychological stress as a risk factor for Alzheimer’s disease (AD). Herein, we examined the relationships between serum cortisol and multimodality brain AD biomarkers in 277 cognitively normal midlife individuals at risk for AD. Overall, higher cortisol was associated with lower total brain volume, lower glucose metabolism (CMRglc) in frontal cortex, and higher β-amyloid (Aβ) load in AD-vulnerable regions; and marginally associated with phosphocreatine to ATP ratios (PCr/ATP) in precuneus and parietal regions. Sex-specific modification effects were noted: in women, cortisol exhibited stronger associations with Aβ load and frontal CMRglc, the latter being more pronounced postmenopause. In men, cortisol exhibited stronger associations with gray matter volume and PCr/ATP measures. Higher cortisol was associated with poorer delayed memory in men but not in women. Results were adjusted for age, Apolipoprotein E (APOE) epsilon 4 status, midlife health factors, and hormone therapy use. These results suggest sex-specific neurophysiological responses to stress, and support a role for stress reduction in AD prevention.

New large neuroimaging studies, such as the Adolescent Brain Cognitive Development study (ABCD) and Human Connectome Project (HCP) Development studies are adopting a new T1-weighted imaging sequence with prospective motion correction (PMC) in favor of the more traditional 3-Dimensional Magnetization-Prepared Rapid Gradient-Echo Imaging (MPRAGE) sequence. Here, we used a developmental dataset (ages 5–21, N = 348) from the Healthy Brain Network (HBN) Initiative to directly compare two widely used MRI structural sequences: one based on the Human Connectome Project (MPRAGE) and another based on the ABCD study (MPRAGE+PMC). We aimed to determine if the morphometric measurements obtained from both protocols are equivalent or if one sequence has a clear advantage over the other. The sequences were also compared through quality control measurements. Inter- and intra-sequence reliability were assessed with another set of participants (N = 71) from HBN that performed two MPRAGE and two MPRAGE+PMC sequences within the same imaging session, with one MPRAGE (MPRAGE1) and MPRAGE+PMC (MPRAGE+PMC1) pair at the beginning of the session and another pair (MPRAGE2 and MPRAGE+PMC2) at the end of the session. Intraclass correlation coefficients (ICC) scores for morphometric measurements such as volume and cortical thickness showed that intra-sequence reliability is the highest with the two MPRAGE+PMC sequences and lowest with the two MPRAGE sequences. Regarding inter-sequence reliability, ICC scores were higher for the MPRAGE1 - MPRAGE+PMC1 pair at the beginning of the session than the MPRAGE1 - MPRAGE2 pair, possibly due to the higher motion artifacts in the MPRAGE2 run. Results also indicated that the MPRAGE+PMC sequence is robust, but not impervious, to high head motion. For quality control metrics, the traditional MPRAGE yielded better results than MPRAGE+PMC in 5 of the 8 measurements. In conclusion, morphometric measurements evaluated here showed high inter-sequence reliability between the MPRAGE and MPRAGE+PMC sequences, especially in images with low head motion. We suggest that studies targeting hyperkinetic populations use the MPRAGE+PMC sequence, given its robustness to head motion and higher reliability scores. However, neuroimaging researchers studying non-hyperkinetic participants can choose either MPRAGE or MPRAGE+PMC sequences, but should carefully consider the apparent tradeoff between relatively increased reliability, but reduced quality control metrics when using the MPRAGE+PMC sequence.