In social animals, the behavioral and hormonal responses to stress can be transmitted from one individual to another through a social transmission process, and conversely, social support ameliorates stress responses, a phenomenon referred to as social buffering. Metaplasticity represents activity-dependent synaptic changes that modulate the ability to elicit subsequent synaptic plasticity. Authentic stress can induce hippocampal metaplasticity, but whether transmitted stress has the same ability remains unknown. Here, using an acute restraint-tailshock stress paradigm, we report that both authentic and transmitted stress in adult male mice trigger metaplastic facilitation of long-term depression (LTD) induction at hippocampal CA1 synapses. Using LTD as a readout of persistent synaptic consequences of stress, our findings demonstrate that, in a male-male dyad, stress transmission happens in nearly half of naïve partners and stress buffering occurs in approximately half of male stressed mice which closely in...

In recent years, several hierarchical extensions of well-known learning algorithms have been proposed. For example, when stimulus-action mappings vary across time or context, the brain may learn two or more stimulus-action mappings in separate modules, and additionally (at a hierarchically higher level) learn to appropriately switch between those modules. However, how the brain mechanistically coordinates neural communication to implement such hierarchical learning, remains unknown. Therefore, the current study tests a recent computational model that proposed how midfrontal theta oscillations implement such hierarchical learning via the principle of binding by synchrony (Sync model). More specifically, the Sync model employs bursts at theta frequency to flexibly bind appropriate task modules by synchrony. 64-channel EEG signal was recorded while 27 human subjects (Female: 21, Male: 6) performed a probabilistic reversal learning task. In line with the Sync model, post-feedback theta power showed a linear re...

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....

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...

Long-term memory (LTM) formation is a critical survival process by which an animal retains information about prior experiences in order to guide future behavior. In the experimentally advantageous marine mollusk Aplysia , LTM for sensitization can be induced by the presentation of two aversive shocks to the animal’s tail. Each of these training trials recruits distinct growth factor signaling systems that promote LTM formation. Specifically, whereas intact TrkB signaling during Trial 1 promotes an initial and transient increase of the immediate early gene apc/ebp mRNA, a prolonged increase in apc/ebp gene expression required for LTM formation requires the addition of TGFβ signaling during Trial 2. Here we explored the molecular mechanisms by which Trial 2 achieves the essential prolonged gene expression of apc/ebp . We find that this prolonged gene expression is not dependent on de novo transcription, but that apc/ebp mRNA synthesized by Trial 1 is post-transcriptionally stabilized by interacting with the ...