The transcription factor CREB is involved in a myriad of cellular functions in the central nervous system. For instance, the role of CREB via phosphorylation at the amino-acid residue Serine (Ser) 133 in expressing plasticity-related genes and activity-dependent neuronal plasticity processes has been extensively demonstrated. However, much less is known about the role of CREB phosphorylation at Ser 142 and 143. Here, we employed a viral vector containing a dominant negative form of CREB, with serine-to-alanine mutations at residue 142 and 143 to specifically block phosphorylation at both sites. We then transfected this vector into primary neurons in vitro or intra-cortically injected it into mice in vivo, to test if these phosphorylation events were important for activity-dependent plasticity. We demonstrated by immunohistochemistry of cortical neuronal cultures that the expression of Arc, a known plasticity-related gene, requires triple phosphorylation of CREB at Ser 133, 142, and 143. Moreover, we record...

The ability to adapt under significant adversity, defined as psychological resilience, is instrumental in preventing stress-related disorders. An important aspect of resilience is the capacity to endure affective distress when in pursuit of goals, also known as distress tolerance. Evidence that links intrinsic baseline interactions within large-scale functional networks with performance under distress remains missing. We hypothesized that the anterior cingulate cortex (ACC) may engage in distress tolerance due to its involvement in attention and emotion regulation. Accordingly, we tested whether behavioral performance under distress is associated with baseline resting-state ACC functional connectivity (FC). Distress tolerance was measured in 97 participants using the behavioral indicator of resiliency to distress (BIRD) task. Analyses contrasted participants who quit the task before its designated termination (n=51) with those who persisted throughout it (n=46). Seed-based FC analysis indicated greater con...

In oscillatory circuits, some actions of neuromodulators depend on the oscillation frequency. However, the mechanisms are poorly understood. We explored this problem by characterizing neuromodulation of the lateral pyloric (LP) neuron of the crab stomatogastric ganglion. Many peptide modulators, including proctolin, activate the same ionic current ( I MI) in stomatogastric neurons. Because I MI is fast and non-inactivating, its peak level does not depend on the temporal properties of neuronal activity. We found, however, that the amplitude and peak time of the proctolin-activated current in LP is frequency-dependent. Because frequency affects the rate of voltage change, we measured these currents with voltage ramps of different slopes and found that proctolin activated two kinetically distinct ionic currents: the known I MI, whose amplitude is independent of ramp slope or direction, and an inactivating current ( I MI-T), which was only activated by positive ramps and whose amplitude increased with increasi...

Adult-onset neurodegenerative diseases are often accompanied by evidence of a chronic inflammation that includes activation of microglial cells and altered levels of brain cytokines. Aspects of this response are likely secondary reactions to neurodegeneration, but for many illnesses the inflammation may itself be an early and even causative disease event. In such cases, the inflammation is referred to as "sterile" as it occurs in the absence of an actual bacterial or viral pathogen. A potent trigger of sterile inflammation in CNS microglia has been shown to be the presence of DNA in the cytoplasm (cytoDNA) induced either by direct DNA damage or by inhibited DNA repair. We have shown that cytoDNA comes from the cell nucleus as a result of insufficient DNA damage repair. Using wild type and Atm-/- mouse microglia, we extend these observations here by showing that its genomic origins are not random, but rather are heavily biased towards transcriptionally inactive, intergenic regions, in particular repetitive ...

Alpha activity (8–14 Hz) is the dominant rhythm in the awake brain, and thought to play an important role in setting the brain’s internal state. Previous work has associated states of decreased alpha power with enhanced neural excitability. However, evidence is mixed on whether and how such excitability enhancement modulates sensory signals of interest versus noise differently, and what, if any, the consequences are for subsequent perception. Here, human subjects (male and female) performed a visual detection task in which we manipulated their decision criteria in a block-wise manner. While our manipulation led to substantial criterion shifts, these shifts were not reflected in pre-stimulus alpha-band changes. Rather, lower pre-stimulus alpha power in occipital-parietal areas improved perceptual sensitivity and enhanced information content decodable from neural activity patterns. Additionally, oscillatory alpha phase immediately before stimulus presentation modulated accuracy. Together, our results suggest...

Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied sensory processing in the cerebellum in a mouse model of autism, knockout for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region upon electrical stimulation of the whisker pad in alert mice ...

To improve future decisions, people should seek information based on the value of information (VOI), which depends on the current evidence and the reward structure of the upcoming decision. When additional evidence is supplied, people should update the VOI to adjust subsequent information seeking, but the neurocognitive mechanisms of this updating process remain unknown. We used a modified beads task to examine how the VOI is represented and updated in the human brain of both sexes. We theoretically derived, and empirically verified, a normative prediction that the VOI depends on decision evidence and is biased by reward asymmetry. Using fMRI, we found that the subjective VOI is represented in the right dorsolateral prefrontal cortex (DLPFC). Critically, this VOI representation was updated when additional evidence was supplied, showing that the DLPFC dynamically tracks the up-to-date VOI over time. These results provide new insights into how humans adaptively seek information in the service of decision-mak...

Different types of tissue injury, such as inflammatory and neuropathic conditions, cause modality-specific alternations on temperature perception. There are profound changes in peripheral sensory neurons after injury, but how patterned neuronal activities in the CNS encode injury-induced sensitization to temperature stimuli is largely unknown. Using in vivo calcium imaging and mouse genetics, we show that formalin- and prostaglandin E2-induced inflammation dramatically increase spinal responses to heating and decrease responses to cooling in male and female mice. The reduction of cold response is largely eliminated on ablation of TRPV1-expressing primary sensory neurons, indicating a crossover inhibition of cold response from the hyperactive heat inputs in the spinal cord. Interestingly, chemotherapy medication oxaliplatin can rapidly increase spinal responses to cooling and suppress responses to heating. Together, our results suggest a push–pull mechanism in processing cold and heat inputs and reveal a sy...

Pain is the major debilitating symptom of osteoarthritis (OA), which is difficult to treat. In OA patients joint tissue damage only poorly associates with pain, indicating other mechanisms contribute to OA pain. Immune cells regulate the sensory system, but little is known about the involvement of immune cells in OA pain. Here, we report that macrophages accumulate in the dorsal root ganglia (DRG) distant from the site of injury in two rodent models of OA. DRG macrophages acquired an M1-like phenotype, and depletion of DRG macrophages resolved OA pain in male and female mice. Sensory neurons innervating the damaged knee joint shape DRG macrophages into an M1-like phenotype. Persisting OA pain, accumulation of DRG macrophages, and programming of DRG macrophages into an M1-like phenotype were independent of Nav1.8 nociceptors. Inhibition of M1-like macrophages in the DRG by intrathecal injection of an IL4-IL10 fusion protein or M2-like macrophages resolved persistent OA pain. In conclusion, these findings re...

Subcortical input engages in cortico-hippocampal information processing. Neurons of the hypothalamic supramammillary nucleus (SuM) innervate the dentate gyrus (DG) by coreleasing two contrasting fast neurotransmitters, glutamate and GABA, and thereby support spatial navigation and contextual memory. However, the synaptic mechanisms by which SuM neurons regulate the DG activity and synaptic plasticity are not well understood. The DG comprises excitatory granule cells (GCs) as well as inhibitory interneurons (INs). Combining optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that the SuM input differentially regulates the activities of different DG neurons in mice of either sex via distinct synaptic mechanisms. Although SuM activation results in synaptic excitation and inhibition in all postsynaptic cells, the ratio of these two components is variable and cell type-dependent. Specifically, dendrite-targeting INs receive predominantly synaptic excitation, whereas soma-targeting ...