Synchronous activity of cortical inhibitory interneurons expressing parvalbumin (PV) underlies expression of cortical γ rhythms. Paradoxically, deficient PV inhibition is associated with increased broadband γ power in the local field potential. Increased baseline broadband γ is also a prominent characteristic in schizophrenia and a hallmark of network alterations induced by NMDAR antagonists, such as ketamine. Whether enhanced broadband γ is a true rhythm, and if so, whether rhythmic PV inhibition is involved or not, is debated. Asynchronous and increased firing activities are thought to contribute to broadband power increases spanning the γ band. Using male and female mice lacking NMDAR activity specifically in PV neurons to model deficient PV inhibition, we here show that neuronal activity with decreased synchronicity is associated with increased prefrontal broadband γ power. Specifically, reduced spike time precision and spectral leakage of spiking activity because of higher firing rates (spike “contami...

The addition of new neurons to existing neural circuits in the adult brain remains of great interest to neurobiology because of its therapeutic implications. The premier model for studying this process has been the hippocampal dentate gyrus in mice, where new neurons are added to mature circuits during adulthood. Notably, external factors such as an enriched environment (EE) and exercise markedly increase hippocampal neurogenesis. Here, we demonstrate that EE acts by increasing fibroblast growth factor receptor (FGFR) function autonomously within neurogenic cells to expand their numbers in adult male and female mice. FGFRs activated by EE signal through their mediators, FGFR substrate (FRS), to induce stem cell proliferation, and through FRS and phospholipase Cγ to increase the number of adult-born neurons, providing a mechanism for how EE promotes adult neurogenesis. SIGNIFICANCE STATEMENT How the environment we live in affects cognition remains poorly understood. In the current study, we explore the mec...

BK calcium-activated potassium channels have complex kinetics because they are activated by both voltage and cytoplasmic calcium. The timing of BK activation and deactivation during action potentials determines their functional role in regulating firing patterns but is difficult to predict a priori. We used action potential clamp to characterize the kinetics of voltage-dependent calcium current and BK current during action potentials in Purkinje neurons from mice of both sexes, using acutely dissociated neurons that enabled rapid voltage clamp at 37°C. With both depolarizing voltage steps and action potential waveforms, BK current was entirely dependent on calcium entry through voltage-dependent calcium channels. With voltage steps, BK current greatly outweighed the triggering calcium current, with only a brief, small net inward calcium current before Ca-activated BK current dominated the total Ca-dependent current. During action potential waveforms, although BK current activated with only a short (∼100 μs...

Epigenetic mechanisms regulate processes of neuroplasticity critical to cocaine-induced behaviors. This includes the Class I histone deacetylase (HDAC) HDAC3, known to act as a negative regulator of cocaine-associated memory formation within the nucleus accumbens (NAc). Despite this, it remains unknown how cocaine alters HDAC3-dependent mechanisms. Here, we profiled HDAC3 expression and activity in total NAc mouse tissue following cocaine exposure. Although chronic cocaine did not affect expression of Hdac3 within the NAc, chronic cocaine did affect promoter-specific changes in HDAC3 and H4K8Ac occupancy. These changes in promoter occupancy correlated with cocaine-induced changes in expression of plasticity-related genes. To causally determine whether cocaine-induced plasticity is mediated by HDAC3's deacetylase activity, we overexpressed a deacetylase-dead HDAC3 point mutant (HDAC3-Y298H-v5) within the NAc of adult male mice. We found that disrupting HDAC3's enzymatic activity altered selective changes in...

Ubiquitin tagging sets protein fate. With a wide range of possible patterns and reversibility, ubiquitination can assume many shapes to meet specific demands of a particular cell across time and space. In neurons, unique cells with functionally distinct axons and dendrites harboring dynamic synapses, the ubiquitin code is exploited at the height of its power. Indeed, wide expression of ubiquitination and proteasome machinery at synapses, a diverse brain ubiquitome, and the existence of ubiquitin-related neurodevelopmental diseases support a fundamental role of ubiquitin signaling in the developing and mature brain. While special attention has been given to dendritic ubiquitin-dependent control, how axonal biology is governed by this small but versatile molecule has been considerably less discussed. Herein, we set out to explore the ubiquitin-mediated spatiotemporal control of an axon's lifetime: from its differentiation and growth through presynaptic formation, function, and pruning.

Animals, including humans, readily learn to avoid harmful and threatening situations by moving in response to cues that predict the threat (e.g., fire alarm, traffic light). During a negatively reinforced sensory-guided locomotor action, known as signaled active avoidance, animals learn to avoid a harmful unconditioned stimulus (US) by moving away when signaled by a harmless conditioned stimulus (CS) that predicts the threat. CaMKII-expressing neurons in the pedunculopontine tegmentum area (PPT) of the midbrain locomotor region have been shown to play a critical role in the expression of this learned behavior, but the activity of these neurons during learned behavior is unknown. Using calcium imaging fiber photometry in freely behaving mice, we show that PPT neurons sharply activate during presentation of the auditory CS that predicts the threat – before onset of avoidance movement. PPT neurons activate further during the succeeding CS-driven avoidance movement, or during the faster US-driven escape moveme...

A visual object is characterized by multiple visual features, including its identity, position and size. Despite the usefulness of identity and nonidentity features in vision and their joint coding throughout the primate ventral visual processing pathway, they have so far been studied relatively independently. Here in both female and male human participants, the coding of identity and nonidentity features was examined together across the human ventral visual pathway. The nonidentity features tested included two Euclidean features (position and size) and two non-Euclidean features (image statistics and spatial frequency content of an image). Overall, identity representation increased and nonidentity feature representation decreased along the ventral visual pathway, with identity outweighing the non-Euclidean but not the Euclidean features at higher levels of visual processing. In 14 convolutional neural networks (CNNs) pretrained for object categorization with varying architecture, depth, and with/without r...

Drosophila odorant receptors (Ors) are ligand gated ion channels composed of a common receptor subunit ORCO (odorant receptor co-receptor) and one of 62 ‘tuning’ receptor subunits that confer odorant specificity to olfactory neuron responses. Like other sensory systems studied to date, exposing Drosophila olfactory neurons to activating ligands results in reduced responses to subsequent exposures through a process called desensitization. We recently showed that phosphorylation of serine 289 on the common odorant receptor subunit ORCO is required for normal peak olfactory neuron responses. Dephosphorylation of this residue occurs upon prolonged odorant exposure, and underlies the slow modulation of olfactory neuron responses we term ‘slow desensitization’. Slow desensitization results in the reduction of peak olfactory neuron responses and flattening of dose-response curves, implicating changes in ORCOS289 phosphorylation state as an important modulator of olfactory neuron responses. Here, we report the ide...

In the best studied cases ( Aplysia feeding, crustacean stomatogastric system), peptidergic modulation is mediated by large numbers of peptides. Furthermore, in Aplysia , excitatory motor neurons release the peptides, obligatorily coupling target activation and modulator release. Vertebrate nervous systems typically contain about a hundred peptide modulators. These data have created a belief that modulation is, in general, complex. The stick insect leg is a well-studied locomotory model system, and the complete stick insect neuropeptide inventory was recently described. We used multiple techniques to comprehensively examine stick insect leg peptidergic modulation. Single-cell mass spectrometry (MS) and immunohistochemistry showed that myoinhibitory peptide (MIP) is the only neuronal (as opposed to hemolymph-borne) peptide modulator of all leg muscles. Leg muscle excitatory motor neurons contained no neuropeptides. Only the common inhibitor (CI) and dorsal unpaired median (DUM) neuron groups, each neuron of...

Expected Utility Theory (EUT), the first axiomatic theory of risky choice, describes choices as a utility maximization process: decision makers assign a subjective value (utility) to each choice option and choose the one with the highest utility. The continuity axiom, central to Expected Utility Theory and its modifications, is a necessary and sufficient condition for the definition of numerical utilities. The axiom requires decision makers to be indifferent between a gamble and a specific probabilistic combination of a more preferred and a less preferred gamble. While previous studies demonstrated that monkeys choose according to combinations of objective reward magnitude and probability, a concept-driven experimental approach for assessing the axiomatically defined conditions for maximizing utility by animals is missing. We experimentally tested the continuity axiom for a broad class of gamble types in 4 male rhesus macaque monkeys, showing that their choice behavior complied with the existence of a nume...