Associative binding is key to normal memory function and is transiently disrupted during periods of post-traumatic amnesia (PTA) following traumatic brain injury (TBI). Electrophysiological abnormalities including low-frequency activity are common following TBI. Here, we investigate associative memory binding during PTA and test the hypothesis that misbinding is caused by pathological slowing of brain activity disrupting cortical communication. Thirty acute moderate-severe TBI patients (25 males; 5 females) and 26 healthy controls (20 males; 6 females) were tested with a precision working memory paradigm requiring the association of object and location information. Electrophysiological effects of TBI were assessed using resting-state EEG in a subsample of 17 patients and 21 controls. PTA patients showed abnormalities in working memory function and made significantly more misbinding errors than patients who were not in PTA and controls. The distribution of localisation responses was abnormally biased by the...

We investigated how environment symmetry shapes the neural processing of direction, by recording directionally tuned retrosplenial neurons in male Lister-hooded rats exploring multi-compartment environments that had different levels of global rotational symmetry. Our hypothesis built on prior observations of twofold symmetry in the directional tuning curves of rats in a globally twofold-symmetric environment. To test whether environment symmetry was the relevant factor shaping the directional responses, here we deployed the same apparatus (two connected rectangular boxes) plus one with fourfold symmetry (a 2x2 array of connected square boxes) and one with onefold symmetry (a circular open-field arena). Consistent with our hypothesis we found many neurons with tuning curve symmetries that mirrored these environment symmetries, having twofold, fourfold or onefold-symmetric tuning respectively. Some cells expressed this pattern only globally (across the whole environment), maintaining singular tuning curves i...

Age-related hearing loss (presbycusis) affects a third of the world’s population. One hallmark of presbycusis is difficulty hearing in noisy environments. Presbycusis can be separated into two components: the aging ear and the aging brain. To date, the role of the aging brain in presbycusis is not well understood. Activity in the primary auditory cortex (A1) during a behavioral task is due to a combination of responses representing the acoustic stimuli, attentional gain, and behavioral choice. Disruptions in any of these aspects can lead to decreased auditory processing. To investigate how these distinct components are disrupted in aging, we performed in vivo 2-photon Ca2+ imaging in both male and female mice (Thy1-GCaMP6s X CBA/CaJ mice) that retain peripheral hearing into old age. We imaged A1 neurons of young-adult (2-6 months) and old mice (16-24 months) during a tone detection task in broadband noise. While young mice performed well, old mice performed worse at low signal-to-noise ratios (SNR). Calciu...

Mnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimer’s disease. We tested if functional connectivity (FC) within the entorhinal-hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and amyloid-β (Aβ) pathology in a sample of 64 cognitively normal human older adults (71.3 ±6.4 years old, 67% female). FC was measured between entorhinal-hippocampal circuit nodes with known anatomic connectivity, as well as within cortical memory networks. Aβ pathology was measured with 18F-florbetapir-PET, and neurodegeneration was assessed with subregional volume from structural MRI. Participants performed both object and spatial versions of a mnemonic discrimination task outside of the scanner and were classified into low- and high-performing groups on each task using a median split. Low object mnemonic discrimination performance was specifically...

Neuropeptide release from dense-core vesicles in Caenorhabditis elegans is promoted by UNC-31, ortholog of the calcium-dependent activator protein for secretion (CAPS). Loss of UNC-31 causes multiple phenotypes in C. elegans including reduced motility, retention of late-stage eggs and reduction in evoked synaptic release. However, the ability to analyze UNC-31 function over discrete timescales and in specific neurons is lacking. Here, we generated and validated a tool to enable UNC-31 expression and spatiotemporal functional analysis. We show that endogenously tagged UNC-31 is expressed in major ganglia and nerve cords from late-embryonic stages through to adult. Using the auxin-inducible degradation system, we depleted UNC-31 post-embryonically from the hermaphrodite nervous system and revealed defects in egg-laying, locomotion and vesicle release that were comparable to unc-31 null mutant animals. In addition, we found that depleting UNC-31 specifically from the BAG sensory neurons causes increased intes...

Oligodendrocytes, the myelinating cell of the central nervous system (CNS), promote rapid action potential conduction along axons. Changes in the geometry of gaps between myelin segments, known as nodes of Ranvier, affect the conduction speed of neuronal impulses and can ultimately alter neural synchronization and circuit function. In contrast to synaptic plasticity, much less is known about how neural activity may affect node of Ranvier structure. Recently, perinodal astrocytes have been shown to remodel nodes of Ranvier by regulating thrombin proteolysis, but it is not known if neural activity influences this process. To test this hypothesis, we used transgenic mice with astrocytic expression of a dominant-negative vesicle-associated membrane protein 2 ([gfap]dnVAMP2) to reduce exocytosis of thrombin inhibitors, modulating astrocytic regulation of paranodal loop attachment to induce nodal remodeling, under normal conditions and in adult mice maintained in darkness from P40-P70. This mechanism of nodal le...

Visuospatial attention is a prerequisite for the performance of visually guided movements: Perceptual discrimination is regularly enhanced at target locations prior to movement initiation. It is known that this attentional prioritization evolves over the time of movement preparation; however, it is not clear whether this build-up simply reflects a time requirement of attention formation or whether, instead, attention build-up reflects the emergence of the movement decision. To address this question, we combined behavioral experiments, psychophysics, and computational decision-making models to characterize the time course of attention build-up during motor preparation. Participants (n = 46, 29 female) executed center-out reaches to one of two potential target locations and reported the identity of a visual discrimination target that occurred concurrently at one of various time-points during movement preparation and execution. Visual discrimination increased simultaneously at the two potential target locatio...

Nucleus basalis magnocellularis (NBM) cholinergic projections to the basolateral amygdala (BLA) regulate the acquisition and consolidation of fear- and anxiety-like behaviors. However, it is unclear whether the alterations in the NBM-BLA circuit promote negative affect during ethanol withdrawal. Therefore, we performed ex vivo whole-cell patch clamp electrophysiology in both the NBM and the BLA of male Sprague-Dawley rats following 10 days of chronic intermittent ethanol (CIE) exposure and 24 hours of withdrawal (WD). We found that CIE exposure and withdrawal enhanced the neuronal excitability of NBM putative ‘cholinergic’ neurons. We subsequently used optogenetics to directly manipulate NBM terminal activity within the BLA and measure cholinergic modulation of glutamatergic afferents and BLA pyramidal neurons. Our findings indicate that CIE and withdrawal upregulate NBM cholinergic facilitation of glutamate release via activation of presynaptic nicotinic acetylcholine receptors. Ethanol withdrawal-induced...

Historically, diabetic retinopathy has been recognized as a vascular disease. Recent clinical evidence suggests the initiation of diabetic retinopathy with neuropathy rather than microangiopathy. However, the molecular mechanism that drives diabetic retinopathy-associated neuropathy remains mostly unexplored. Here, we reported progressive diabetic retinopathy defects in blood glucose levels, shortening of cone segments and uncoupled appearance of retinal vascular abnormalities from pdx1 +/− mutants zebrafish to glucose-treated pdx1 +/− mutants zebrafish of both sexes. Further single-cell transcriptomic analysis revealed cones as the most vulnerable retinal neuron type that underwent three developmentally progressive cell states (States 1-3), predominantly present in WT animals, pdx1 +/− mutants , and glucose-treated pdx1 +/− mutants , respectively. Mechanistically, the expression of hcn1 was progressively decreased in cones during its transition from State 1 to State 3. Furthermore, genetic hcn1 disruption...