Prosocial behavior is pivotal to our society. Guilt aversion, which describes the tendency to reduce the discrepancy between a partner’s expectation and his/her actual outcome, drives human prosocial behavior as does well-known inequity aversion. Although women are reported to be more inequity averse than men, gender differences in guilt aversion remain unexplored. Here, we conducted a functional magnetic resonance imaging (fMRI) study ( n  =   52) and a large-scale online behavioral study ( n  =   4723) of a trust game designed to investigate guilt and inequity aversions. The fMRI study demonstrated that men exhibited stronger guilt aversion and recruited right dorsolateral prefrontal cortex (DLPFC)-ventromedial PFC (VMPFC) connectivity more for guilt aversion than women, while VMPFC-dorsal medial PFC (DMPFC) connectivity was commonly used in both genders. Furthermore, our regression analysis of the online behavioral data collected with Big Five and demographic factors replicated the gender differences an...

Secreted amyloid-β (Aβ) peptide forms neurotoxic oligomeric assemblies thought to cause synaptic deficits associated with Alzheimer’s disease (AD). Soluble Aβ oligomers (Aβo) directly bind to neurons with high affinity and block plasticity mechanisms related to learning and memory, trigger loss of excitatory synapses and eventually cause cell death. While Aβo toxicity has been intensely investigated, it remains unclear precisely where Aβo initially binds to the surface of neurons and whether sites of binding relate to synaptic deficits. Here, we used a combination of live cell, super-resolution and ultrastructural imaging techniques to investigate the kinetics, reversibility and nanoscale location of Aβo binding. Surprisingly, Aβo does not bind directly at the synaptic cleft as previously thought but, instead, forms distinct nanoscale clusters encircling the postsynaptic membrane with a significant fraction also binding presynaptic axon terminals. Synaptic plasticity deficits were observed at Aβo-bound syn...

Water restriction is commonly used to motivate rodents to perform behavioral tasks; however, its effects on hydration and stress hormone levels are unknown. Here, we report daily body weight and bi-weekly packed red blood cell volume and corticosterone (CORT) in adult male rats across 80 days for three commonly used water restriction schedules. We also assessed renal adaptation to water restriction using postmortem histologic evaluation of renal medulla. A control group received ad libitum water. After one week of water restriction, rats on all restriction schedules resumed similar levels of growth relative to the control group. Normal hydration was observed, and water restriction did not drive renal adaptation. An intermittent restriction schedule was associated with an increase in CORT relative to the control group. However, intermittent restriction evokes a stress response which could affect behavioral and neurobiological results. Our results also suggest that stable motivation in behavioral tasks may o...

Vision loss from diseases of the outer retina, such as age-related macular degeneration, is among the leading causes of irreversible blindness in the world today. The goal of retinal prosthetics is to replace the photo-sensing function of photoreceptors lost in these diseases with optoelectronic hardware to electrically stimulate patterns of retinal activity corresponding to vision. To enable high-resolution retinal prosthetics, the scale of stimulating electrodes must be significantly decreased from current designs; however, this reduces the amount of stimulating current that can be delivered. The efficacy of subretinal stimulation at electrode sizes suitable for high visual acuity retinal prosthesis are not well understood, particularly within the safe charge injection limits of electrode materials. Here, we measure retinal ganglion cell (RGC) responses in a mouse model of blindness to evaluate the stimulation efficacy of 10, 20, and 30 μm diameter iridium oxide electrodes within the electrode charge inj...

Excitatory amino acid transporters (EAATs) remove glutamate from the synaptic cleft. In the retina, EAAT1 and EAAT2 are considered the major glutamate transporters. However, it has not yet been possible to determine how EAAT5 shapes the retinal light responses because of the lack of a selective EAAT5 blocker or EAAT5 knock-out (KO) animal model. In this study, EAAT5 was found to be expressed in a punctate manner close to release sites of glutamatergic synapses in the mouse retina. Light responses from retinae of wild-type (WT) and of a newly generated model with a targeted deletion of EAAT5 (EAAT5−/−) were recorded in vitro using multielectrode arrays (MEAs). Flicker resolution was considerably lower in EAAT5−/− retinae than in WT retinae. The close proximity to the glutamate release site makes EAAT5 an ideal tool to improve temporal information processing in the retina by controlling information transfer at glutamatergic synapses.

Hyperglycemia is a comorbidity in 60–80% of stroke patients; nevertheless, neuroprotective drugs like NMDA receptor (NMDAR) antagonists are typically assessed in normoglycemic animals at the preclinical stage before they are approved to enter clinical trials. Interestingly, as a possible explanation for the translational failure of NMDAR antagonists, it was recently reported that stroke occurring during nighttime causes smaller infarctions in rodents and therefore has a smaller window for neuroprotection. To investigate why stroke occurring during different circadian phases confers a difference in severity, we reanalyzed the published source data and found that some mice that were used in the daytime have higher blood glucose than mice that were used in the nighttime. We then repeated the experiments but found no difference in blood glucose concentration or infarct volume regardless of the circadian phase during which stroke occurs. On the other hand, induction of hyperglycemia by glucose injection reprodu...

Studies in animals have demonstrated a strong relationship between cortical and hippocampal activity, and autonomic tone. However, the extent, distribution, and nature of this relationship have not been investigated with intracranial recordings in humans during sleep. Cortical and hippocampal population neuronal firing was estimated from high γ band activity (HG) from 70 to 110 Hz in local field potentials (LFPs) recorded from 15 subjects (nine females) during nonrapid eye movement (NREM) sleep. Autonomic tone was estimated from heart rate variability (HRV). HG and HRV were significantly correlated in the hippocampus and multiple cortical sites in NREM stages N1–N3. The average correlation between HG and HRV could be positive or negative across patients given anatomic location and sleep stage and was most profound in lateral temporal lobe in N3, suggestive of greater cortical activity associated with sympathetic tone. Patient-wide correlation was related to δ band activity (1–4 Hz), which is known to be co...

Select neuronal populations display steady rhythmic neuronal firing that provides tonic excitation to drive downstream networks and behaviors. In noradrenergic neurons of the locus coeruleus (LC), circadian neurons of the suprachiasmatic nucleus (SCN), and CO2/H+-activated neurons of the brainstem retrotrapezoid nucleus (RTN), large subthreshold membrane potential oscillations contribute to the pacemaker-like action potential discharge. The oscillations and firing in LC and SCN involve contributions from leak sodium (NALCN) and L-type calcium channels while recent work from RTN suggested an additional pivotal role for a secondary calcium-activated and voltage-gated cationic current sensitive to TRPM4 channel blockers. Here, we tested whether TRPM4 contributes to subthreshold oscillations in mouse LC and SCN. By RNAscope in situ hybridization, Trpm4 transcripts were detected in both cell groups. In whole-cell recordings from acute slice preparations, prominent voltage-dependent membrane potential oscillatio...

Inflammatory cells including macrophages and microglia synthesize and release the oxysterol, 25-hydroxycholesterol (25HC), which has antiviral and immunomodulatory properties. Here, we examined the effects of lipopolysaccharide (LPS), an activator of innate immunity, on 25HC production in microglia, and the effects of LPS and 25HC on CA1 hippocampal synaptic plasticity and learning. In primary microglia, LPS markedly increases expression of cholesterol 25-hydroxylase (Ch25h), the key enzyme involved in 25HC synthesis, and increases the levels of secreted 25HC. Wild type microglia produced higher levels of 25HC than Ch25h knockout (KO) microglial with or without LPS. LPS treatment also disrupts long-term potentiation (LTP) in hippocampal slices via induction of a form of NMDA receptor-dependent metaplasticity. The inhibitory effects of LPS on LTP were mimicked by exogenous 25HC, and were not observed in slices from Ch25h KO mice. In vivo, LPS treatment also disrupts LTP and inhibits one-trial learning in wi...

Sensory environments are commonly characterized by specific physical features, which sensory systems might exploit using dedicated processing mechanisms. In the tactile sense, one such characteristic feature is frictional movement, which gives rise to short-lasting (<10 ms), information-carrying integument vibrations. Rather than generic integrative encoding (i.e., averaging or spectral analysis capturing the “intensity” and “best frequency”), the tactile system might benefit from, what we call a “temporally local” coding scheme that instantaneously detects and analyzes shapes of these short-lasting features. Here, by employing analytic psychophysical measurements, we tested whether the prerequisite of temporally local coding exists in the human tactile system. We employed pulsatile skin indentations at the fingertip that allowed us to trade manipulation of local pulse shape against changes in global intensity and frequency, achieved by adding pulses of the same shape. We found that manipulation of local p...