Understanding the long-term effects of stress on brain function is crucial for understanding the mechanisms of depression. The BALB/c mouse strain has high susceptibility to stress and is thus an effective model for depression. The long-term effects of repeated social defeat stress (SDS) on BALB/c mice, however, are not clear. Here, we investigated the effects of repeated SDS in male BALB/c mice over the subsequent two weeks. Some defeated mice immediately exhibited social avoidance, whereas anxiety-like behavior was only evident at later periods. Furthermore, defeated mice segregated into two groups based on the level of social avoidance, namely, avoidant and nonavoidant mice. The characteristic of avoidance or nonavoidance in each individual was not fixed over the two weeks. In addition, we developed a semi-automated method for analyzing c-Fos expression in the mouse brain to investigate the effect of repeated SDS on brain activity more than two weeks after the end of the stress exposure. Following socia...

The neural underpinnings of humans’ ability to process faces and how it changes over typical development have been extensively studied using paradigms where face stimuli are oversimplified, isolated, and decontextualized. The prevalence of this approach, however, has resulted in limited knowledge of face processing in ecologically valid situations, in which faces are accompanied by contextual information at multiple time scales. In the present study, we use a naturalistic movie paradigm to investigate how neuromagnetic activation and phase synchronization elicited by faces from movie scenes in humans differ between children and adults. We used MEG data from 22 adults (6 females, 3 left handed; mean age, 27.7 ± 5.28 years) and 20 children (7 females, 1 left handed; mean age, 9.5 ± 1.52 years) collected during movie viewing. We investigated neuromagnetic time-locked activation and phase synchronization elicited by movie scenes containing faces in contrast to other movie scenes. Statistical differences betwee...

Voltage-gated calcium channel Cav2.1 undergoes Ca2+-dependent facilitation and inactivation, which are important in short-term synaptic plasticity. In presynaptic terminals, Cav2.1 forms large protein complexes that include synaptotagmins. Synaptotagmin-7 (Syt-7) is essential to mediate short-term synaptic plasticity in many synapses. Here, based on evidence that Cav2.1 and Syt-7 are both required for short-term synaptic facilitation, we investigated the direct interaction of Syt-7 with Cav2.1 and probed its regulation of Cav2.1 function. We found that Syt-7 binds specifically to the α1A subunit of Cav2.1 through interaction with the synaptic-protein interaction (synprint) site. Surprisingly, this interaction enhances facilitation in paired-pulse protocols and accelerates the onset of facilitation. Syt-7α induces a depolarizing shift in the voltage dependence of activation of Cav2.1 and slows Ca2+-dependent inactivation, whereas Syt-7β and Syt-7γ have smaller effects. Our results identify an unexpected, is...

Inhibitory neurons take on many forms and functions. How this diversity contributes to memory function is not completely known. Previous formal studies indicate inhibition differentiated by local and global connectivity in associative memory networks functions to rescale the level of retrieval of excitatory assemblies. However, such studies lack biological details such as a distinction between types of neurons (excitatory and inhibitory), unrealistic connection schemas, and nonsparse assemblies. In this study, we present a rate-based cortical model where neurons are distinguished (as excitatory, local inhibitory, or global inhibitory), connected more realistically, and where memory items correspond to sparse excitatory assemblies. We use this model to study how local-global inhibition balance can alter memory retrieval in associative memory structures, including naturalistic and artificial structures. Experimental studies have reported inhibitory neurons and their subtypes uniquely respond to specific stim...

Because of their ease of use, adeno-associated viruses (AAVs) are indispensable tools for much of neuroscience. Yet AAVs have been used relatively little to study the identities and connectivity of peripheral sensory neurons, principally because methods to selectively target peripheral neurons have been limited. The introduction of the AAV-PHP.S capsid with enhanced tropism for peripheral neurons ([Chan et al., 2017][1]) offered a solution, which we further elaborate here. Using AAV-PHP.S with GFP or mScarlet fluorescent proteins, we show that the mouse sensory ganglia for cranial nerves V, VII, IX, and X are targeted. Pseudounipolar neurons of both somatic and visceral origin, but not satellite glia, express the reporters. One week after virus injection, ≈66% of geniculate ganglion neurons were transduced. Fluorescent reporters were transported along the central and peripheral axons of these sensory neurons, permitting visualization of terminals at high resolution, and in intact, cleared brain using light...

Brain aging is a natural process that involves structural and functional changes that lead to cognitive decline, even in healthy subjects. This detriment has been associated with NMDA receptor (NMDAR) hypofunction because of a reduction in the brain levels of D-serine, the endogenous NMDAR co-agonist. However, it is not clear whether D-serine supplementation could be used as an intervention to reduce or reverse age-related brain alterations. In the present work, we aimed to analyze the D-serine effect on aging-associated alterations in cellular and large-scale brain systems that could support cognitive flexibility in rats. We found that D-serine supplementation reverts the age-related decline in cognitive flexibility, frontal dendritic spine density, and partially restored large-scale functional connectivity without inducing nephrotoxicity; instead, D-serine restored the thickness of the renal epithelial cells that were affected by age. Our results suggest that D-serine could be used as a therapeutic targe...

Vocal learning in songbirds is mediated by a highly localized system of interconnected forebrain regions, including recurrent loops that traverse the cortex, basal ganglia, and thalamus. This brain-behavior system provides a powerful model for elucidating mechanisms of vocal learning, with implications for learning speech in human infants, as well as for advancing our understanding of skill learning in general. A long history of experiments in this area has tested neural responses to playback of different song stimuli in anesthetized birds at different stages of vocal development. These studies have demonstrated selectivity for different song types that provide neural signatures of learning. In contrast to the ease of obtaining responses to song playback in anesthetized birds, song-evoked responses in awake birds are greatly reduced or absent, indicating that behavioral state is an important determinant of neural responsivity. Song-evoked responses can be elicited during sleep as well as anesthesia, and th...

The dorsal raphe (DR) nucleus contains many tyrosine hydroxylase (TH)-positive neurons which are regarded as dopaminergic (DA) neurons. These DA neurons in the DR and periaqueductal gray (PAG) region (DADR-PAG neurons) are a subgroup of the A10 cluster, which is known to be heterogeneous. This DA population projects to the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) and has been reported to modulate various affective behaviors. To characterize, the histochemical features of DADR-PAG neurons projecting to the CeA and BNST in mice, the current study combined retrograde labeling with Fluoro-Gold (FG) and histological techniques, focusing on TH, dopamine transporter (DAT), vasoactive intestinal peptide (VIP), and vesicular glutamate transporter 2 (VGlut2). To identify putative DA neurons, DAT-Cre::Ai14 mice were used. It was observed that DATDR-PAG neurons consisted of the following two subpopulations: TH+/VIP– and TH–/VIP+ neurons. The DAT+/TH–/VIP+ subpopulation w...

Dendritic spines have diverse morphologies, with a wide range of head and neck sizes, and these morphologic differences likely generate different functional properties. To explore how this morphologic diversity differs across species and ages we analyzed 3D confocal reconstructions of ∼8000 human spines and ∼1700 mouse spines, labeled by intracellular injections in fixed tissue. Using unsupervised algorithms, we computationally separated spine heads and necks and systematically measured morphologic features of spines in apical and basal dendrites from cortical pyramidal cells. Human spines had unimodal distributions of parameters, without any evidence of morphologic subtypes. Their spine necks were longer and thinner in apical than in basal spines, and spine head volumes of an 85-year-old individual were larger than those of a 40-year-old individual. Human spines had longer and thicker necks and larger head volumes than mouse spines. Our results indicate that human spines form part of a continuum, are larg...

The activity of primary auditory cortex (A1) neurons is modulated not only by sensory inputs but also by other task-related variables in associative learning. However, it is unclear how A1 neural activity changes dynamically in response to these variables during the learning process of associative memory tasks. Therefore, we developed an associative memory task using auditory stimuli in rats. In this task, rats were required to associate tone frequencies (high and low) with a choice of ports (right or left) to obtain a reward. The activity of A1 neurons in the rats during the learning process of the task was recorded. A1 neurons increased their firing rates either when the rats were presented with a high or low tone (frequency-selective cells) before they chose either the left or right port (choice-direction cells), or when they received a reward after choosing either the left or right port (reward-direction cells). Furthermore, the proportion of frequency-selective cells and reward-direction cells increas...