Humans do not have an accurate representation of probability information in the environment but distort it in a surprisingly stereotyped way (“probability distortion”), as shown in a wide range of judgment and decision-making tasks. Many theories hypothesize that humans automatically compensate for the uncertainty inherent in probability information (“representational uncertainty”) and probability distortion is a consequence of uncertainty compensation. Here we examined whether and how the representational uncertainty of probability is quantified in the human brain and its relevance to probability distortion behavior. Human subjects (13 female and 9 male) kept tracking the relative frequency of one color of dot in a sequence of dot arrays while their brain activity was recorded by magnetoencephalography (MEG). We found converging evidence from both neural entrainment and time-resolved decoding analysis that a mathematically-derived measure of representational uncertainty is automatically computed in the br...

Ketamine is known to have a rapid and lasting antidepressant effect. Recent studies have shown that ketamine exerts it rapid antidepressant effect by blocking burst firing in the lateral habenula (LHb). Whether the sustained antidepressant effect of ketamine occurs through the same mechanism has not been explored. Here, using male rats, we found that local infusion of (R,S)-ketamine into the LHb resulted in a rapid antidepressant-like effect 1 hour after infusion, which almost returned to baseline levels after 24 hours. Intra-LHb injection of (S)-ketamine also showed a significant antidepressant-like effect 1 hour after injection, which recovered at 24 hours. No significant antidepressant-like effect was found at 1 hour or 24 hours after administration of (R)-ketamine into the LHb. Injection of (2R,6R)-hydroxynorketamine (HNK), a ketamine metabolite, into the LHb did not result in any obvious antidepressant-like effect 1 hour or 24 hours after injection. Systemic administration of (R,S)-ketamine (intraperi...

How neurons encode natural stimuli is a fundamental question for sensory neuroscience. In the early visual system, standard encoding models assume that neurons linearly filter incoming stimuli through their receptive fields, but artificial stimuli, such as contrast-reversing gratings, often reveal nonlinear spatial processing. We investigated to what extent such nonlinear processing is relevant for the encoding of natural images in retinal ganglion cells in mice of either sex. We found that standard linear receptive field models yielded good predictions of responses to flashed natural images for a subset of cells, but failed to capture the spiking activity for many others. Cells with poor model performance displayed pronounced sensitivity to fine spatial contrast and local signal rectification as the dominant nonlinearity. By contrast, sensitivity to high-frequency contrast-reversing gratings, a classical test for nonlinear spatial integration, was not a good predictor of model performance and thus did not...

Dynamic changes in motor abilities and motivated behaviors occur during the juvenile and adolescent periods. The striatum is a subcortical nucleus critical to action selection, motor learning and reward processing. Its tonically active cholinergic interneuron (ChI) is an integral regulator of the synaptic activity of other striatal neurons, as well as afferent axonal projections of midbrain dopamine neurons; however, little is known about its development. Here, we report that ChI spontaneous activity increases during postnatal development of male and female mice, concomitant with a decreased afterhyperpolarization. We characterized the postnatal development of four currents that contribute to the spontaneous firing rate of ChIs, including ISK, IA, Ih and INaP. We demonstrated that the developmental increase in INaP drives increased ChI firing rates during the postnatal period and can be reversed by the INaP inhibitor, ranolazine. We next addressed whether immature cholinergic signaling may lead to function...

We used a semantic feature matching task combined with multivoxel pattern decoding to test contrasting accounts of the role of the default mode network (DMN) in cognitive flexibility. By one view, DMN and multiple-demand cortex have opposing roles in cognition – with DMN and multiple-demand regions within the dorsal attention network (DAN) supporting internal and external cognition respectively. Consequently, while multiple-demand regions can decode current goal information, semantically-relevant DMN regions might decode conceptual similarity irrespective of task demands. Alternatively, DMN regions, like multiple-demand cortex, might show sensitivity to changing task demands, since both networks dynamically alter their patterns of connectivity depending on the context. Our task required human participants (any gender) to integrate conceptual knowledge with changing task goals, such that successive decisions were based on different features of the items (colour, shape and size). This allowed us to simultane...

Clinical and experimental data from the last nine decades indicate that the preoptic area of the hypothalamus is a critical node in a brain network that controls sleep onset and homeostasis. By contrast, we recently reported that a group of glutamatergic neurons in the lateral and medial preoptic area increases wakefulness, challenging the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic. However, the precise role of these subcortical neurons in the control of behavioral state transitions and cortical dynamics remains unknown. Therefore, in this study we used conditional expression of excitatory hM3Dq receptors in these preoptic glutamatergic (Vglut2+) neurons and show that their activation initiates wakefulness, decreases non-rapid eye movement (NREM) sleep, and causes a persistent suppression of rapid eye movement (REM) sleep. We also demonstrate for the first time that activation of these preoptic glutamatergic neurons causes a high degree of NREM sleep fragmen...

Synaptophysin (syp) is a major integral membrane protein of secretory vesicles. Previous work has demonstrated functions for syp in synaptic vesicle cycling, endocytosis, and synaptic plasticity, but the role of syp in the process of membrane fusion during Ca2+-triggered exocytosis remains poorly understood. Furthermore, although syp resides on both large dense-core and small synaptic vesicles, its role in dense-core vesicle function has received less attention compared to synaptic vesicle function. To explore the role of syp in membrane fusion and dense-core vesicle function, we used amperometry to measure catecholamine release from single vesicles in male and female mouse chromaffin cells with altered levels of syp and the related tetraspanner protein synaptogyrin (syg). Knocking out syp slightly reduced the frequency of vesicle fusion events below wild-type levels, but knocking out both syp and syg reduced the frequency two-fold. Knocking out both proteins stabilized initial fusion pores, promoted fusio...

Dynamic control of protein degradation via the ubiquitin proteasome system is thought to play a crucial role in neuronal function and synaptic plasticity. The proteasome subunit Rpt6, an AAA ATPase subunit of the 19S regulatory particle, has emerged as an important site for regulation of 26S proteasome function in neurons. Phosphorylation of Rpt6 on serine 120 (S120) can stimulate the catalytic rate of substrate degradation by the 26S proteasome and this site is targeted by the plasticity-related kinase calcium/calmodulin-dependent kinase II (CaMKII), making it an attractive candidate for regulation of proteasome function in neurons. Several in vitro studies have shown that altered Rpt6 S120 phosphorylation can affect the structure and function of synapses. To evaluate the importance of Rpt6 S120 phosphorylation in vivo , we created two mouse models which feature mutations at S120 that block or mimic phosphorylation at this site. We find that peptidase and ATPase activities are upregulated in the phospho-m...

Past social experience affects the circuitry responsible for producing and interpreting current behaviors. The social behavior network (SBN) is a candidate neural ensemble to investigate the consequences of early-life social isolation. The SBN interprets and produces social behaviors, such as vocalizations, through coordinated patterns of activity (functional connectivity) between its multiple nuclei. However, the SBN is relatively unexplored with respect to murine vocal processing. The serotonergic system is sensitive to past experience and innervates many nodes of the SBN; therefore, we tested whether serotonin signaling interacts with social experience to affect patterns of immediate early gene (IEG; cFos) induction in the male SBN following playback of social vocalizations. Male mice were separated into either social housing of three mice per cage or into isolated housing at 18–24 d postnatal. After 28–30 d in housing treatment, mice were parsed into one of three drug treatment groups: control, fenflur...

Experimental models of epilepsy are useful to identify potential mechanisms of epileptogenesis, seizure genesis, comorbidities, and treatment efficacy. The kainic acid (KA) model is one of the most commonly used. Several modes of administration of KA exist, each producing different effects in a strain, species, gender, and age-dependent manner. In this review, we discuss the advantages and limitations of the various forms of KA administration (systemic, intrahippocampal, and intranasal), as well as the histological, electrophysiological, and behavioral outcomes in different strains and species. We attempt a personal perspective and discuss areas where work is needed. The diversity of KA models and their outcomes offers researchers a rich palette of phenotypes, which may be relevant to specific traits found in patients with temporal lobe epilepsy. Significance statement This review aims to help researchers use a knowledge-based approach to study specific aspects of human epilepsy phenotypes. We focus on ...