Circadian rhythms are biological processes that cycle across 24 hours and regulate many facets of neurophysiology, including learning and memory. Circadian variation in spatial memory task performance is well-documented; however, the effect of sex across circadian time remains unclear. Additionally, little is known regarding the impact of time-of-day on hippocampal neuronal physiology. Here, we investigated the influence of both sex and time-of-day on hippocampal neurophysiology and memory in mice. Performance on the object location memory (OLM) task depended on both circadian time and sex, with memory enhanced at night in males but during the day in females. Long-term synaptic potentiation (LTP) magnitude at CA3-CA1 synapses was greater at night compared to day in both sexes. Next, we measured spontaneous synaptic excitation and inhibition onto CA1 pyramidal neurons. Frequency and amplitude of inhibition was greater during the day compared to night, regardless of sex. Frequency and amplitude of excitation...

Categorization is an essential cognitive and perceptual process for decision making and recognition. The posterior parietal cortex (PPC), particularly the lateral intraparietal (LIP) area has been suggested to transform visual feature encoding into abstract categorical representations. By contrast, areas closer to sensory input, such as the middle temporal (MT) area, encode stimulus features but not more abstract categorical information during categorization tasks. Here, we compare the contributions of the medial superior temporal (MST) and LIP areas in category computation by recording neuronal activity in both areas from two male rhesus macaques trained to perform a visual motion categorization task. MST is a core motion processing area interconnected with MT, and often considered an intermediate processing stage between MT and LIP. Here we show that MST exhibits robust decision-correlated motion category encoding and working memory encoding similar to LIP, suggesting that MST plays a substantial role in...

Jixiang Zhang, Jazzmine M. Junigan, Ronnie Trinh, Annemieke Kavelaars, Cobi J. Heijnen, et al. (see pages [7862–7874][1]) Chemotherapy-induced peripheral neuropathy (CIPN) increases pain sensitivity and can produce spontaneous pain in the distal appendages of many cancer patients. The symptoms

Mutations in the gene encoding vesicle-associated membrane protein B (VAPB) cause a familial form of amyotrophic lateral sclerosis (ALS). Expression of an ALS-related variant of vapb ( vapbP58S ) in Drosophila motor neurons results in morphologic changes at the larval neuromuscular junction (NMJ) characterized by the appearance of fewer, but larger, presynaptic boutons. Although diminished microtubule stability is known to underlie these morphologic changes, a mechanism for the loss of presynaptic microtubules has been lacking. By studying flies of both sexes, we demonstrate the suppression of vapbP58S -induced changes in NMJ morphology by either a loss of endoplasmic reticulum (ER) Ca2+ release channels or the inhibition Ca2+/calmodulin (CaM)-activated kinase II (CaMKII). These data suggest that decreased stability of presynaptic microtubules at vapbP58S NMJs results from hyperactivation of CaMKII because of elevated cytosolic [Ca2+]. We attribute the Ca2+ dyshomeostasis to delayed extrusion of cytosolic ...

Cochlear amplification enables the enormous dynamic range of hearing through amplifying cochlear responses to low- to moderate-level sounds and compressing them to loud sounds. Amplification is attributed to voltage-dependent electromotility of mechanosensory outer hair cells (OHCs) driven by changing voltages developed across their cell membranes. At low frequencies, these voltage changes are dominated by intracellular receptor potentials (RPs). However, OHC membranes have electrical low-pass filter properties that attenuate high-frequency RPs, which should potentially attenuate amplification of high-frequency cochlear responses and impede high-frequency hearing. We made in vivo intracellular and extracellular electrophysiological measurements from the organ of Corti of male and female mice of the CBA/J strain, with excellent high-frequency hearing, and from the CD-1 mouse strain, which has sensitive hearing below 12 kHz but loses high-frequency hearing within a few weeks postpartum. The CD-1 mouse strain...

Across species, including humans, elevated levels of brain estrogen receptor (ER) α are associated with enhanced cognitive aging, even in the absence of circulating estrogens. In rodents, short-term estrogen treatment, such as that commonly used in the menopausal transition, results in long-term increases in ERα levels in the hippocampus, leading to enhanced memory long after termination of estrogen treatment. However, mechanisms by which increased levels of brain ERα enhances cognitive aging remain unclear. Here we demonstrate in aging female rats that insulin-like growth factor-1 (IGF-1), which can activate ER via ligand-independent mechanisms, requires concomitant synthesis of brain-derived neuroestrogens to phosphorylate ERα via MAPK signaling, ultimately resulting in enhanced memory. In a rat model of menopause involving long-term ovarian hormone deprivation, hippocampal neuroestrogen activity decreases, altering IGF-1 activity and resulting in impaired memory. However, this process is reversed by sho...

α2δ-1 (encoded by the Cacna2d1 gene) is a newly discovered NMDA receptor–interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin), frequently used for treating patients with neuropathic pain. Nerve injury causes sustained α2δ-1 upregulation in the dorsal root ganglion (DRG), which promotes NMDA receptor synaptic trafficking and activation in the spinal dorsal horn, a hallmark of chronic neuropathic pain. However, little is known about how nerve injury initiates and maintains the high expression level of α2δ-1 to sustain chronic pain. Here, we show that nerve injury caused histone hyperacetylation and diminished enrichment of histone deacetylase-2 (HDAC2), but not HDAC3, at the Cacna2d1 promoter in the DRG. Strikingly, Hdac2 knockdown or conditional knockout in DRG neurons in male and female mice consistently induced long-lasting mechanical pain hypersensitivity, which was readily reversed by blocking NMDA receptors, inhibiting α2δ-1 with gabapentin, or disruptin...

Neuroimaging studies of individuals with autism spectrum disorders (ASD) consistently find an aberrant pattern of “reduced” laterality in brain networks that support functions related to social communication and language. However, it is unclear how the underlying functional organization of these brain networks is altered in ASD individuals. We tested four models of “reduced” laterality in a social-communication network in seventy ASD individuals (14 females) and a control group of the same number of tightly matched typically developing (TD) individuals (19 females) using high quality resting-state fMRI data and a method of measuring patterns of functional laterality across the brain. We found that a functionally defined social-communication network exhibited the typical pattern of left laterality in both groups, while there was a significant increase in within- relative to across-hemisphere connectivity of homotopic regions in the right hemisphere in ASD individuals. Furthermore, greater within- relative t...

Traumatic brain injury (TBI) is associated with chronic psychiatric complications and increased risk for development of neurodegenerative pathology. Aged individuals account for most TBI-related hospitalizations and deaths. Nonetheless, neurobiological mechanisms that underlie worsened functional outcomes after TBI in the elderly remain unclear. Therefore, this study aimed to identify pathways that govern differential responses to TBI with age. Here, adult (2 mo) and aged (16-18 mo) male C57BL/6 mice were subjected to diffuse brain injury (midline fluid percussion), and cognition, gliosis, and neuroinflammation were determined 7 or 30 days post injury (dpi). Cognitive impairment was evident 7 dpi, independent of age. There was enhanced morphological restructuring of microglia and astrocytes 7 dpi in the cortex and hippocampus of aged mice compared to adults. Transcriptional analysis revealed robust age-dependent amplification of cytokine/chemokine, complement, innate immune, and interferon-associated infla...