Faculty Bibliography

Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.

Deficient cognitive top-down executive control has long been hypothesized to underlie inattention and impulsivity in attention-deficit/hyperactivity disorder (ADHD). However, top-down cognitive dysfunction explains a modest proportion of the ADHD phenotype whereas the salience of emotional dysregulation is being noted increasingly. Together, these two types of dysfunction have the potential to account for more of the phenotypic variance in patients diagnosed with ADHD. We develop this idea and suggest that top-down dysregulation constitutes a gradient extending from mostly non-emotional top-down control processes (i.e., "cool" executive functions) to mainly emotional regulatory processes (including "hot" executive functions). While ADHD has been classically linked primarily to the former, conditions involving emotional instability such as borderline and antisocial personality disorder are closer to the other. In this model, emotional subtypes of ADHD are located at intermediate levels of this gradient. Neuroanatomically, gradations in "cool" processing appear to be related to prefrontal dysfunction involving dorsolateral prefrontal cortex (dlPFC) and caudal anterior cingulate cortex (cACC), while "hot" processing entails orbitofrontal cortex and rostral anterior cingulate cortex (rACC). A similar distinction between systems related to non-emotional and emotional processing appears to hold for the basal ganglia (BG) and the neuromodulatory effects of the dopamine system. Overall we suggest that these two systems could be divided according to whether they process non-emotional information related to the exteroceptive environment (associated with "cool" regulatory circuits) or emotional information related to the interoceptive environment (associated with "hot" regulatory circuits). We propose that this framework can integrate ADHD, emotional traits in ADHD, borderline and antisocial personality disorder into a related cluster of mental conditions.

As information propagates along the ventral visual hierarchy, neuronal responses become both more specific for particular image features and more tolerant of image transformations that preserve those features. Here, we present evidence that neurons in area V2 are selective for local statistics that occur in natural visual textures, and tolerant of manipulations that preserve these statistics. Texture stimuli were generated by sampling from a statistical model, with parameters chosen to match the parameters of a set of visually distinct natural texture images. Stimuli generated with the same statistics are perceptually similar to each other despite differences, arising from the sampling process, in the precise spatial location of features. We assessed the accuracy with which these textures could be classified based on the responses of V1 and V2 neurons recorded individually in anesthetized macaque monkeys. We also assessed the accuracy with which particular samples could be identified, relative to other statistically matched samples. For populations of up to 100 cells, V1 neurons supported better performance in the sample identification task, whereas V2 neurons exhibited better performance in texture classification. Relative to V1, the responses of V2 show greater selectivity and tolerance for the representation of texture statistics.

The mediodorsal thalamus (MDT) is a higher-order corticocortical thalamic nucleus involved in cognition and memory. However, anatomically, the MDT is also the primary site of olfactory representation in the thalamus, receiving strong inputs from olfactory cortex and having reciprocal connections with orbitofrontal cortex (OFC). Nonetheless, its role in olfaction remains unclear. Here, we recorded single units in the MDT, as well as local field potentials in the MDT, piriform cortex (PCX), and OFC in rats performing a two-alternative odor discrimination task. We show that subsets of MDT units display odorant selectivity during sampling, as well as encoding of spatio-motor aspects of the task. Furthermore, the olfactory trans-thalamic network rapidly switches functional connectivity between MDT and cortical areas depending on current task demands, with, for example, MDT-PCX coupling enhanced during odor sampling and MDT-OFC coupling enhanced during the decision/goal approach compared with baseline and presampling. These results demonstrate MDT representation of diverse sensorimotor components of an olfactory task. SIGNIFICANCE STATEMENT: The mediodorsal thalamus (MDT) is the major olfactory thalamic nucleus and links the olfactory archicortex with the prefrontal neocortex. The MDT is well known to be involved in higher-order cognitive and memory functions, but its role in olfaction is poorly understood. Here, using single-unit and local field potential analyses, we explored MDT function during an odor-guided decision task in rats. We describe MDT odor and multisensory coding and demonstrate behavior-dependent functional connectivity within the MDT/sensory cortex/prefrontal cortex network. Our results suggest a rich representation of olfactory and other information within MDT required to perform this odor-guided task. Our work opens a new model system for understanding MDT function and exploring the important role of MDT in cortical-cortical communication.

Studies have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes in culture. However, evidence demonstrating current can passively spread across scar tissue in the intact heart remains elusive. We hypothesize electrotonic conduction occurs across non-myocyte gaps in the heart and is partly mediated by Connexin43 (Cx43). We investigated whether non-myocytes in ventricular scar tissue are electrically connected to surrounding myocardial tissue in wild type and fibroblast-specific protein-1 driven conditional Cx43 knock-out mice (Cx43fsp1KO). Electrical coupling between the scar and uninjured myocardium was demonstrated by injecting current into the myocardium and recording depolarization in the scar through optical mapping. Coupling was significantly reduced in Cx43fsp1KO hearts. Voltage signals were recorded using microelectrodes from control scars but no signals were obtained from Cx43fsp1KO hearts. Recordings showed significantly decreased amplitude, depolarized resting membrane potential, increased duration and reduced upstroke velocity compared to surrounding myocytes, suggesting that the non-excitable cells in the scar closely follow myocyte action potentials. These results were further validated by mathematical simulations. Optical mapping demonstrated that current delivered within the scar could induce activation of the surrounding myocardium. These data demonstrate non-myocytes in the scar are electrically coupled to myocytes, and coupling depends on Cx43 expression.

Alzheimer's disease (AD) is characterized by a decrease in the enzymatic activity of the enzyme acetylcholinesterase (AChE). AChE is expressed as multiple splice variants, which may serve both cholinergic degradative functions and non-cholinergic functions unrelated with their capacity to hydrolyze acetylcholine. We have recently demonstrated that a prominent pool of enzymatically inactive AChE protein exists in the AD brain. In this study, we analyzed protein and transcript levels of individual AChE variants in human frontal cortex from AD patients by western blot analysis using specific anti-AChE antibodies and by quantitative real-time PCR (qRT-PCR). We found similar protein and mRNA levels of the major cholinergic "tailed"-variant (AChE-T) and the anchoring subunit, proline-rich membrane anchor (PRiMA-1) in frontal cortex obtained from AD patients and non-demented controls. Interestingly, we found an increase in the protein and transcript levels of the non-cholinergic "readthrough" AChE (AChE-R) variants in AD patients compared to controls. Similar increases were detected by western blot using an antibody raised against the specific N-terminal domain, exclusive of alternative N-extended variants of AChE (N-AChE). In accordance with a subset of AChE-R monomers that display amphiphilic properties that are upregulated in the AD brain, we demonstrate that the increase of N-AChE species is due, at least in part, to N-AChE-R variants. In conclusion, we demonstrate selective alterations in specific AChE variants in AD cortex, with no correlation in enzymatic activity. Therefore, differential expression of AChE variants in AD may reflect changes in the pathophysiological role of AChE, independent of cholinergic impairment or its role in degrading acetylcholine.

Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite beta-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of beta-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of beta-hydroxybutyrate. Electrophysiological measurements indicate that beta-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.

Organisms are surrounded throughout life by chemically complex odors. How individuals process an odorant within a mixture or a mixture as a whole is a key question in neuroethology and chemical senses. This question is addressed here by using newborn rabbits, which can be rapidly conditioned to a new stimulus by single association with the mammary pheromone. After conditioning to ethyl maltol (odorant B), pups behaviorally respond to B and an A'B' mixture (68/32 ratio) but not to ethyl isobutyrate (odorant A) or an AB mixture (30/70 ratio). This suggests elemental and configural perception of A'B' and AB, respectively. We then explored the neural substrates underlying the processing of these mixtures with the hypothesis that processing varies according to perception. Pups were pseudoconditioned or conditioned to B on postnatal day 3 before exposure to B, A'B' or AB on day 4. Fos expression was not similar between groups (mainly in the olfactory bulb and posterior piriform cortex) suggesting a differential processing of the stimuli that might reflect either stimulus complexity or conditioning effect. Thus, the ratio of components in A'B' vs AB leads to differential activation of the olfactory system which may contribute to elemental and configural percepts of these mixtures. In addition, together with recent behavioral data, this highlights that configural perception occurs even in relatively immature animals, emphasizing the value of the newborn rabbit for exploration of odor mixture processing from molecules to brain and behavior.