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...

Spontaneous bursts of electrical activity in the developing auditory system arise within the cochlea prior to hearing onset and propagate through future sound processing circuits of the brain to promote maturation of auditory neurons. Studies in isolated cochleae revealed that this intrinsically generated activity is initiated by ATP release from inner supporting cells (ISCs), resulting in activation of purinergic autoreceptors, K+ efflux and subsequent depolarization of inner hair cells (IHCs). However, it is unknown when this activity emerges or whether different mechanisms induce activity during distinct stages of development. Here we show that spontaneous electrical activity in mouse cochlea from both sexes emerges within ISCs during the late embryonic period, preceding the onset of spontaneous correlated activity in IHCs and spiral ganglion neurons (SGNs), which begins at birth and follows a base to apex developmental gradient. At all developmental ages, pharmacological inhibition of P2Y1 purinergic r...

Spatial selective listening and auditory choice underlie important processes including attending to a speaker at a cocktail party and knowing how (or if) to respond. To examine task encoding and relative timing of potential neural substrates underlying these behaviors, we developed a spatial selective detection paradigm for monkeys, and recorded activity in primary auditory cortex (AC), dorsolateral prefrontal cortex (dlPFC) and the basolateral amygdala (BLA). A comparison of neural responses among these three areas showed that, as expected, AC encoded the side of the cue and target characteristics before dlPFC and BLA. Interestingly, AC also encoded the monkey’s choice before dlPFC and around the time of BLA. Generally, BLA showed weak responses to all task features except the choice. Decoding analyses suggested that errors followed from a failure to encode the target stimulus in both AC and dlPFC, but again, these differences arose earlier in AC. The similarities between AC and dlPFC responses were aboli...

We test the hypothesis that the stability and precision of context and visual discrimination memories depend upon interactions between the hippocampus (HPC) and other memory storage networks. In four experiments we tested the properties of memories acquired in the absence of the HPC. Long-Evans male rats were exclusively used in all experiments. Experiment 1 evaluated acquisition and retention of context fear memories in rats with prior partial or complete HPC damage. Confirming an earlier report (Zelikowsky, et al., 2012) a very small but statistically reliable slowing in a single session of context fear conditioning was found after HPC damage. In contrast, retention of context fear memory was normal after HPC damage up to 30 days after learning. In Experiment 2 we found that discrimination between a context paired with foot shocks and a different context never paired with foot shock was retained normally for 15 days. In Experiment 3 we replicated the finding of intact context discrimination for at least ...

The BAD-BAX-caspase-3 cascade is a canonical apoptosis pathway. Macroautophagy (‘autophagy’ hereinafter) is a process by which organelles and aggregated proteins are delivered to lysosomes for degradation. Here, we report a new function of the BAD-BAX-caspase-3 cascade and autophagy in the control of synaptic vesicle pools. We found that in hippocampal neurons of male mice, the BAD-BAX-caspase-3 pathway regulates autophagy, which in turn limits the size of synaptic vesicle pools and influences the kinetics of activity-induced depletion and recovery of synaptic vesicle pools. Moreover, the caspase-autophagy pathway is engaged by fear conditioning to facilitate associative fear learning and memory. This work identifies a new mechanism for controlling synaptic vesicle pools, and a novel, non-apoptotic, presynaptic function of the BAD-BAX-caspase-3 cascade. SIGNIFICANCE STATEMENT: Despite the importance of synaptic vesicles for neurons, little is known about how the size of synaptic vesicle pools is maintai...

In addition to producing a classical excitatory postsynaptic current via activation of synaptic NMDA receptors (NMDARs), glutamate in the brain also induces a tonic NMDAR receptor current (INMDA) via activation of extrasynaptic NMDARs (eNMDARs). However, since Mg2+ blocks NMDARs in non-depolarized neurons, the potential contribution of eNMDARs to the overall neuronal excitation/inhibition balance remains unknown. Here, we demonstrate that chronic (7-day) salt loading (SL) recruited NR2D subunit-containing NMDARs to generate an Mg2+-resistant tonic INMDA in non-depolarized (Vh, -70 mV) vasopressin (VP) (but not oxytocin (OT)) supraoptic nucleus (SON) neurons in male rodents. Conversely, in euhydrated and 3-day SL mice, Mg2+-resistant tonic INMDA was not observed. Pharmacological and genetic intervention of NR2D subunits blocked the Mg2+-resistant tonic INMDA in VP neurons under SL conditions, while an NR2B antagonist unveiled Mg2+-sensitive tonic INMDA but not Mg2+-resistant tonic INMDA. In the EU-group VP ...

There are significant neurogenic and inflammatory influences on blood pressure, yet the role played by each of these processes in the development of hypertension is unclear. Tumor necrosis factor alpha (TNFα) has emerged as a critical modulator of blood pressure and neural plasticity, however the mechanism by which TNFα signaling contributes to the development of hypertension is uncertain. We present evidence that the TNFα type 1 receptor (TNFR1) plays a key role in heightened glutamate signaling following slow-pressor angiotensin II (AngII) in the hypothalamic paraventricular nucleus (PVN), a key central coordinator of blood pressure control. Fourteen-day administration of a slow-pressor dose of angiotensin II (AngII) in male mice was associated with transcriptional and post-transcriptional (increased plasma membrane affiliation) regulation of TNFR1 in the PVN. Further, TNFR1 was shown to be critical for elevated NMDA-mediated excitatory currents in sympathoexcitatory PVN neurons following AngII infusion....

Speech processing relies on interactions between auditory and motor systems and is asymmetrically organized in the human brain. The left auditory system is specialized for processing of phonemes, whereas the right is specialized for processing of pitch changes in speech affecting prosody. In speakers of tonal languages, however, processing of pitch (i.e., tone) changes that alter word meaning is left-lateralized indicating that linguistic function and language experience shape speech processing asymmetries. Here, we investigated the asymmetry of motor contributions to auditory speech processing in male and female speakers of tonal and non-tonal languages. We temporarily disrupted the right or left speech motor cortex using transcranial magnetic stimulation and measured the impact of these disruptions on auditory discrimination (mismatch negativity) responses to phoneme and tone changes in sequences of syllables using electroencephalography. We found that the effect of motor disruptions on processing of ton...