Activity

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 α (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 following angiotensin II (AngII) infusion the TNFα type 1 receptor (TNFR1) plays a key role in heightened glutamate signaling in the hypothalamic paraventricular nucleus (PVN), a key central coordinator of blood pressure control. Fourteen day administration of a slow-pressor dose of 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. Finally, silencing PVN TNFlly, TNFR1 silencing in the PVN inhibits elevated blood pressure induced by AngII. These results point to a critical role for hypothalamic TNFR1 signaling in hypertension.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. PDS0330 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, nonapoptotic, 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 maintained under basal conditions and regulated by neural activity. This study identifies a new mechanism for the control of synaptic vesicle pools, and a new, nonapoptotic function of the BAD-BAX-caspase-3 pathway in presynaptic terminals. Additionally, it indicates that autophagy is not only a homeostatic mechanism to maintain the integrity of cells and tissues, but also a process engaged by neural activity to regulate synaptic vesicle pools for optimal synaptic responses, learning, and memory.We test the hypothesis that the stability and precision of context and visual discrimination memories depend on 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 d 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 d. In experiment 3, we replicated the finding of intact context discrimination for at least 15 d in rats who display a significant impairment in acquisition of place learning in the Morris water task (MWT). In final experiment using an appetitive object discrimination task, we showed normal retention of the discrimination for at least 30 d after training in rats with complete HPC damage. These finding score against the idea that non HPC memory storage requires a period of interaction with HPC to establish a stable, precise memory.SIGNIFICANCE STATEMENT Contrary to expectations from systems memory consolidation, we find that in the absence of a functional hippocampus (HPC) context and visual memories are formed rapidly and exhibit normal persistence and precision. The findings suggest that the HPC is not obligatory for these features of long-term memories.Spatial selective listening and auditory choice underlie important processes including attending to a speaker at a cocktail party and knowing how (or whether) to respond. To examine task encoding and the 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 choice of the monkey 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 abolished during passive sensory stimulation with identical trial conditions, suggesting that the robust sensory encoding in dlPFC is contextually gated. Thus, counter to a strictly PFC-driven decision process, in this spatial selective listening task AC neural activity represents the sensory and decision information before dlPFC. Unlike in the visual domain, in this auditory task, the BLA does not appear to be robustly involved in selective spatial processing.SIGNIFICANCE STATEMENT We examined neural correlates of an auditory spatial selective listening task by recording single-neuron activity in behaving monkeys from the amygdala, dorsolateral prefrontal cortex, and auditory cortex. We found that auditory cortex coded spatial cues and choice-related activity before dorsolateral prefrontal cortex or the amygdala. Auditory cortex also had robust delay period activity. Therefore, we found that auditory cortex could support the neural computations that underlie the behavioral processes in the task.