Metabolic state can alter olfactory sensitivity, but it is unknown whether the activity of the olfactory bulb (OB) may fine tune metabolic homeostasis. Our objective was to use CRISPR gene editing in male and female mice to enhance the excitability of mitral/tufted projection neurons (M/TCs) of the OB to test for improved metabolic health. Ex vivo slice recordings of MCs in CRISPR mice confirmed increased excitability due the targeted loss of Kv1.3 channels, which resulted in a less negative resting membrane potential (RMP), enhanced action potential (AP) firing, and insensitivity to the selective channel blocker margatoxin (MgTx). CRISPR mice exhibited enhanced odor discrimination using a habituation/dishabituation paradigm. CRISPR mice were challenged for 25 weeks with a moderately high-fat (MHF) diet, and compared with littermate controls, male mice were resistance to diet-induced obesity (DIO). Female mice did not exhibit DIO. CRISPR male mice gained less body weight, accumulated less white adipose tis...

For many decades, synaptic plasticity was believed to be restricted to excitatory transmission. However, in recent years, this view started to change, and now it is recognized that GABAergic synapses show distinct forms of activity-dependent long-term plasticity, but the underlying mechanisms remain obscure. Herein, we asked whether signaling mediated by β1 or β3 subunit-containing integrins might be involved in regulating the efficacy of GABAergic synapses, including the NMDA receptor-dependent inhibitory long-term potentiation (iLTP) in the hippocampus. We found that activation of β3 integrin with fibrinogen induced a stable depression, whereas inhibition of β1 integrin potentiated GABAergic synapses at CA1 pyramidal neurons in male mice. Additionally, compounds that interfere with the interaction of β1 or β3 integrins with extracellular matrix blocked the induction of NMDA-iLTP. In conclusion, we provide the first evidence that integrins are key players in regulating the endogenous modulatory mechanisms...

The posteromedial cortex (PMC) is a major hub of the brain's default mode network, and is implicated in a broad range of internally driven cognitions, including visuospatial working memory. However, its precise contribution to these cognitive processes remains unclear. Using MEG, we measured PMC activity in healthy human participants (young adults of both sexes) while they performed a visuospatial working memory task. Multivariate pattern classification analyses revealed stimulus-related information during encoding and retrieval in a set of a priori defined cortical ROIs, including prefrontal, occipital, and ventrotemporal cortices, in addition to PMC. We measured the extent to which this stimulus information was exchanged between areas in an information flow analysis, measuring Granger-causal relationships between areas over time. Consistent with the visual nature of the task, information from occipital cortex shaped other regions across most epochs. However, the PMC shaped object representations in occip...

When making a turn at a familiar intersection, we know what items and landmarks will come into view. These perceptual expectations, or predictions, come from our knowledge of the context; however, it is unclear how memory and perceptual systems interact to support the prediction and reactivation of sensory details in cortex. To address this, human participants learned the spatial layout of animals positioned in a cross maze. During fMRI, participants of both sexes navigated between animals to reach a target, and in the process saw a predictable sequence of five animal images. Critically, to isolate activity patterns related to item predictions, rather than bottom-up inputs, one-fourth of trials ended early, with a blank screen presented instead. Using multivariate pattern similarity analysis, we reveal that activity patterns in early visual cortex, posterior medial regions, and the posterior hippocampus showed greater similarity when seeing the same item compared with different items. Further, item effects...

The nervous system is under tight energy constraints and must represent information efficiently. This is particularly relevant in the dorsal part of the medial superior temporal area (MSTd) in primates where neurons encode complex motion patterns to support a variety of behaviors. A sparse decomposition model based on a dimensionality reduction principle known as non-negative matrix factorization (NMF) was previously shown to account for a wide range of monkey MSTd visual response properties. This model resulted in sparse, parts-based representations that could be regarded as basis flow fields, a linear superposition of which accurately reconstructed the input stimuli. This model provided evidence that the seemingly complex response properties of MSTd may be a by-product of MSTd neurons performing dimensionality reduction on their input. However, an open question is how a neural circuit could carry out this function. In the current study, we propose a spiking neural network (SNN) model of MSTd based on evo...

Shiyi Li, Shuangmei Ma, Danyang Wang, Hejing Zhang, Yunzhu Li, et al. (see pages [5930–5943][1]) Cooperation allows groups to gain rewards that would be difficult to obtain by individuals working alone. To sustain cooperation, groups often punish members that try to reap rewards without

Human society operates on large-scale cooperation. However, individual differences in cooperativeness and incentives to free ride on others' cooperation make large-scale cooperation fragile and can lead to reduced social welfare. Thus, how individual cooperation spreads through human social networks remains puzzling from ecological, evolutionary, and societal perspectives. Here, we identify oxytocin and costly punishment as biobehavioral mechanisms that facilitate the propagation of cooperation in social networks. In three laboratory experiments ( n = 870 human participants: 373 males, 497 females), individuals were embedded in heterogeneous networks and made repeated decisions with feedback in games of trust ( n = 342), ultimatum bargaining ( n = 324), and prisoner's dilemma with punishment ( n = 204). In each heterogeneous network, individuals at central positions (hub nodes) were given intranasal oxytocin (or placebo). Giving oxytocin (vs matching placebo) to central individuals increased their trust an...

Recent studies using intracellular recordings in awake behaving mice revealed that cortical network states, defined based on membrane potential features, modulate sensory responses and perceptual outcomes. Single cell intracellular recordings are difficult and have low yield compared to extracellular recordings of population signals, such as local field potentials (LFPs). However, it is currently unclear how to identify these behaviorally-relevant network states from the LFP. We used simultaneous LFP and intracellular recordings in the somatosensory cortex of awake mice to design a network state classification from the LFP, the Network State Index (NSI). We used the NSI to analyze the relationship between single-cell (intracellular) and population (LFP) signals over different network states of wakefulness. We found that graded levels of population signal faithfully predicted the levels of single cell depolarization in non-rhythmic regimes whereas, in delta ([2-4 Hz]) oscillatory regimes, the graded levels ...

Synaptotagmin-1 (Syt1) is a vesicular calcium sensor required for synchronous neurotransmitter release, composed of a single-pass transmembrane domain linked to two C2 domains (C2A and C2B) that bind calcium, acidic lipids, and SNARE proteins that drive fusion of the synaptic vesicle with the plasma membrane. Despite its essential role, how Syt1 couples calcium entry to synchronous release is poorly understood. Calcium binding to C2B is critical for synchronous release, and C2B additionally binds the SNARE complex. The C2A domain is also required for Syt1 function, but it is not clear why. Here, we asked what critical feature of C2A may be responsible for its functional role and compared this to the analogous feature in C2B. We focused on highly conserved poly-lysine patches located on the sides of C2A (K189-192) and C2B (K324-327). We tested effects of charge-neutralization mutations in either region (Syt1K189-192A and Syt1K326-327A) side by side to determine their relative contributions to Syt1 function ...

Following tissue injury, latent sensitization (LS) of nociceptive signaling can persist indefinitely, kept in remission by compensatory µ-opioid receptor constitutive activity (MORCA) in the dorsal horn of the spinal cord. To demonstrate LS, we conducted plantar incision in mice and then waited 3–4 weeks for hypersensitivity to resolve. At this time (remission), systemic administration of the opioid receptor antagonist/inverse agonist naltrexone reinstated mechanical and heat hypersensitivity. We first tested the hypothesis that LS extends to serotonergic neurons in the rostral ventral medulla (RVM) that convey pronociceptive input to the spinal cord. We report that in male and female mice, hypersensitivity was accompanied by increased Fos expression in serotonergic neurons of the RVM, abolished on chemogenetic inhibition of RVM 5-HT neurons, and blocked by intrathecal injection of the 5-HT3R antagonist ondansetron; the 5-HT2AR antagonist MDL-11 939 had no effect. Second, to test for MORCA, we microinjecte...