Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type-1a receptors (AT1aR) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male AT1aR-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally-delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while e...

The dentate gyrus (DG) controls information flow into the hippocampus and is critical for learning, memory, pattern separation, and spatial coding, while DG dysfunction is associated with neuropsychiatric disorders. Despite its importance, the molecular mechanisms regulating DG neural circuit assembly and function remain unclear. Here, we identify the Rac-GEF Tiam1 as an important regulator of DG development and associated memory processes. In the hippocampus, Tiam1 is predominantly expressed in the DG throughout life. Global deletion of Tiam1 in male mice results in DG granule cells with simplified dendritic arbors, reduced dendritic spine density, and diminished excitatory synaptic transmission. Notably, DG granule cell dendrites and synapses develop normally in Tiam1 knockout (KO) mice, resembling wildtype mice at postnatal day 21 (P21), but fail to stabilize, leading to dendrite and synapse loss by P42. These results indicate that Tiam1 promotes DG granule cell dendrite and synapse stabilization late i...

The formation of memories that contain information about the specific time and place of acquisition, which are commonly referred to as “autobiographical” or “episodic” memories, critically relies on the hippocampus and on a series of interconnected structures located in the medial temporal lobe of the mammalian brain. The observation that adults retain very few of these memories from the first years of their life has fueled a long-standing debate on whether infants can make the types of memories that in adults are processed by the hippocampus-dependent memory system, and whether the hippocampus is involved in learning and memory processes early in life. Recent evidence shows that, even at a time when its circuitry is not yet mature, the infant hippocampus is able to produce long-lasting memories. However, the ability to acquire and store such memories relies on molecular pathways and network-based activity dynamics different from the adult system, which mature with age. The mechanisms underlying the format...

Asparagine endopeptidase (AEP) is a lysosomal protease implicated in the pathology of Alzheimer’s disease (AD). It is known to cleave the axonal microtubule associated protein, Tau, and amyloid precursor protein (APP), both of which might impede axon regeneration following peripheral nerve injury. Active AEP, AEP-cleaved fragments of Tau (Tau N368), and APP (APP N585) were found in injured peripheral nerves. In AEP null mice, elongation of regenerating axons after sciatic nerve transection and repair was increased relative to wild type (WT) controls. Compound muscle action potentials (M responses) were restored in reinnervated muscles twice as fast after injury in AEP knockout mice as WT controls. Neurite elongation in cultures of adult dorsal root ganglion neurons derived from AEP knockout mice was increased significantly relative to cultures from wild type controls. In AEP knockout mice exposed to one hour of 20 Hz electrical stimulation at the time of nerve injury, no further enhancement of axon regener...

Task-trained artificial recurrent neural networks (RNNs) provide a computational modeling framework of increasing interest and application in computational, systems, and cognitive neuroscience. RNNs can be trained, using deep learning methods, to perform cognitive tasks used in animal and human experiments, and can be studied to investigate potential neural representations and circuit mechanisms underlying cognitive computations and behavior. Widespread application of these approaches within neuroscience has been limited by technical barriers in use of deep learning software packages to train network models. Here we introduce PsychRNN, an accessible, flexible, and extensible Python package for training RNNs on cognitive tasks. Our package is designed for accessibility, for researchers to define tasks and train RNN models using only Python and NumPy without requiring knowledge of deep learning software. The training backend is based on TensorFlow and is readily extensible for researchers with TensorFlow kno...

Source memory improves substantially during childhood. This improvement is thought to be closely related to hippocampal maturation. As previous studies have mainly used cross-sectional designs to assess relations between source memory and hippocampal function, it remains unknown whether changes in the brain precede improvements in memory or vice versa. To address this gap, the current study used an accelerated longitudinal design (n=200, 100 males) to follow 4- and 6-year-old human children for 3 years. We traced developmental changes in source memory and intrinsic hippocampal functional connectivity and assessed differences between the 4- and 6-year-old cohorts in the predictive relations between source memory changes and intrinsic hippocampal functional connectivity in the absence of a demanding task. Consistent with previous studies, there were age-related increases in source memory and intrinsic functional connectivity between the hippocampus and cortical regions known to be involved during memory enco...

Early life stress (ELS) is associated with a higher risk of psychopathologies in adulthood, such as depression, which may be related to persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to evaluate the effects of ELS on the functioning of the HPA axis in clinical and experimental situations. Clinically, patients with current depressive episodes, with and without ELS, and healthy controls, composed the sample. Subjects took a capsule containing placebo, fludrocortisone, prednisolone, dexamethasone or spironolactone followed by an assessment of plasma cortisol the morning after. Experimentally, male Wistar rats were submitted to ELS protocol based on variable, unpredictable stressors from postnatal day (P) 1 to P21. On P65 animals were behaviorally evaluated through the forced swimming test (FST). At P68, pharmacological challenges started, using mifepristone, dexamethasone, spironolactone or fludrocortisone, and corticosterone levels were determined 3 hours after injectio...

The activity and the metabolism of the brain change rhythmically during the day/night cycle. Such rhythmicity is also observed in cultured neurons from the suprachiasmatic nucleus, which is a critical center in rhythm maintenance. However, this issue has not been extensively studied in cultures from areas less involved in timekeeping, as the hippocampus. Using neurons cultured from the hippocampi of newborn rats (both male and female), we observed significant time-dependent changes in global activity, in synaptic vesicle dynamics, in synapse size, and in synaptic mRNA amounts. A transcriptome analysis of the neurons, performed at different times over 24 hours, revealed significant changes only for RNA-binding motif 3 (Rbm3). RBM3 amounts changed especially in synapses. RBM3 knock-down altered synaptic vesicle dynamics and changed the neuronal activity patterns. This procedure also altered local translation in synapses, albeit it left the global cellular translation unaffected. We conclude that hippocampal ...

Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin ( HTT ) gene. Therapeutics that lower HTT have shown preclinical promise and are being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. We have reported that mutant HTT (mHTT) in the cerebrospinal fluid (CSF) of HD patients correlates with clinical measures, including disease burden as well as motor and cognitive performance. We have also shown that lowering HTT in the brains of HD mice results in correlative reduction of mHTT in the CSF, prompting the use of this measure as an exploratory marker of target engagement in clinical trials. In this study, we investigate the mechanisms of mHTT clearance from the brain in adult mice of both sexes to elucidate the significance of therapy-induced CSF mHTT changes. We demonstrate that although neurodegeneration increases CSF mHTT concentrations, mHTT is also present in the CSF of mice in the abs...

Integrating information across different senses is a central feature of human perception. Previous research suggests that multisensory integration is shaped by a context-dependent and largely adaptive interplay between stimulus-driven bottom-up and top-down endogenous influences. One critical question concerns the extent to which this interplay is sensitive to the amount of available cognitive resources. In the present study we investigated the influence of limited cognitive resources on audiovisual integration by measuring high-density EEG in healthy participants performing the sound-induced flash illusion (SIFI) and a verbal n-back task (0-back, low load and 2-back, high load) in a dual-task design. In the SIFI, the integration of a flash with two rapid beeps can induce the illusory perception of two flashes. We found that high compared with low load increased illusion susceptibility and modulated neural oscillations underlying illusion-related crossmodal interactions. Illusion perception under high load...