The paraventricular nucleus of the thalamus (PVT) is increasingly being recognized as a critical node linking stress detection to the emergence of adaptive behavioral responses to stress. However, despite growing evidence implicating the PVT in stress processing, the neural mechanisms by which stress impacts PVT neurocircuitry and promotes stressed states remain unknown. Here we show that stress exposure drives a rapid and persistent reduction of inhibitory transmission onto projection neurons of the posterior PVT (pPVT). This stress-induced disinhibition of the pPVT was associated with a locus coeruleus-mediated rise in the extracellular concentration of dopamine in the midline thalamus, required the function of dopamine D2 receptors on PVT neurons, and increased sensitivity to stress. Our findings define the locus coeruleus as an important modulator of PVT function: by controlling the inhibitory tone of the pPVT, it modulates the excitability of pPVT projection neurons and controls stress responsivity.

Despite recent advances in optogenetics, it remains challenging to manipulate gene expression in specific populations of neurons. We present a dual-protein switch system, Cal-Light, that translates neuronal-activity-mediated calcium signaling into gene expression in a light-dependent manner. In cultured neurons and brain slices, we show that Cal-Light drives expression of the reporter EGFP with high spatiotemporal resolution only in the presence of both blue light and calcium. Delivery of the Cal-Light components to the motor cortex of mice by viral vectors labels a subset of excitatory and inhibitory neurons related to learned lever-pressing behavior. By using Cal-Light to drive expression of the inhibitory receptor halorhodopsin (eNpHR), which responds to yellow light, we temporarily inhibit the lever-pressing behavior, confirming that the labeled neurons mediate the behavior. Thus, Cal-Light enables dissection of neural circuits underlying complex mammalian behaviors with high spatiotemporal precision.

Key points• The intrinsic excitability of a hippocampal CA3 pyramidal cell (CA3-PC), but not CA1-PC, is enhanced by repetitive somatic firing at a physiologically relevant frequency (10 Hz for 2 s).• Such an excitability change is mediated by the Ca 2+ -and Src family kinase-dependent endocytosis of D-type K + channel subunit Kv1.2.• We provide evidence that the surface expression of D-type K + channels is higher in the distal apical dendrites than in the proximal apical dendrites in CA3-PCs.• These results help us understand neuronal computational mechanisms underlying the cognitive functions of the hippocampal CA3 area.Abstract The intrinsic excitability of neurons plays a critical role in the encoding of memory at Hebbian synapses and in the coupling of synaptic inputs to spike generation. It has not been studied whether somatic firing at a physiologically relevant frequency can induce intrinsic plasticity in hippocampal CA3 pyramidal cells (CA3-PCs). Here, we show that a conditioning train of 20 action potentials (APs) at 10 Hz causes a persistent reduction in the input conductance and an acceleration of the AP onset time in CA3-PCs, but not in CA1-PCs. Induction of such long-term potentiation of intrinsic excitability (LTP-IE) was accompanied by a reduction in the D-type K + current, and was abolished by the inhibition of endocytosis or protein tyrosine kinase (PTK). Consistently, the CA3-PCs from Kv1.2 knock-out mice displayed no LTP-IE with the same conditioning. Furthermore, the induction of LTP-IE depended on the back-propagating APs (bAPs) and intact distal apical dendrites. These results indicate that LTP-IE is mediated by the internalization of Kv1.2 channels from the distal regions of apical dendrites, which is triggered by bAP-induced dendritic Ca 2+ signalling and the consequent activation of PTK.

Key pointsr We investigated the cellular mechanisms underlying mossy fibre-induced heterosynaptic long-term potentiation of perforant path (PP) inputs to CA3 pyramidal cells.r Here we show that this heterosynaptic potentiation is mediated by downregulation of Kv1.2 channels.r The downregulation of Kv1.2 preferentially enhanced PP-evoked EPSPs which occur at distal apical dendrites.r Such enhancement of PP-EPSPs required activation of dendritic Na + channels, and its threshold was lowered by downregulation of Kv1.2.r Our results may provide new insights into the long-standing question of how mossy fibre inputs constrain the CA3 network to sparsely represent direct cortical inputs.Abstract A short high frequency stimulation of mossy fibres (MFs) induces long-term potentiation (LTP) of direct cortical or perforant path (PP) synaptic inputs in hippocampal CA3 pyramidal cells (CA3-PCs). However, the cellular mechanism underlying this heterosynaptic modulation remains elusive. Previously, we reported that repetitive somatic firing at 10 Hz downregulates Kv1.2 in the CA3-PCs. Here, we show that MF inputs induce similar somatic firing and downregulation of Kv1.2 in the CA3-PCs. The effect of Kv1.2 downregulation was specific to PP synaptic inputs that arrive at distal apical dendrites. We found that the somatodendritic expression of Kv1.2 is polarized to distal apical dendrites. Compartmental simulations based on this finding suggested that passive normalization of synaptic inputs and polarized distributions of dendritic ionic channels may facilitate the activation of dendritic Na + channels preferentially at distal apical dendrites. Indeed, partial block of dendritic Na + channels using 10 nM tetrodotoxin brought back the enhanced PP-evoked excitatory postsynaptic potentials (PP-EPSPs) to the baseline level. These results indicate that activity-dependent downregulation of Kv1.2 in CA3-PCs mediates MF-induced heterosynaptic LTP of PP-EPSPs by facilitating activation of Na + channels at distal apical dendrites.J. H. Hyun and K. Eom authors contributed equally to this study.

Repetitive action potentials (APs) in hippocampal CA3 pyramidal cells (CA3-PCs) backpropagate to distal apical dendrites, and induce calcium and protein tyrosine kinase (PTK)-dependent downregulation of Kv1.2, resulting in long-term potentiation of direct cortical inputs and intrinsic excitability (LTP-IE). When APs were elicited by direct somatic stimulation of CA3-PCs from rodents of either sex, only a narrow window of distal dendritic [Ca 2ϩ ] allowed LTP-IE because of Ca 2ϩ-dependent coactivation of PTK and protein tyrosine phosphatase (PTP), which renders non-mossy fiber (MF) inputs incompetent in LTP-IE induction. High-frequency MF inputs, however, could induce LTP-IE at high dendritic [Ca 2ϩ ] of the window. We show that MF input-induced Zn 2ϩ signaling inhibits postsynaptic PTP, and thus enables MF inputs to induce LTP-IE at a wide range of [Ca 2ϩ ] i values. Extracellular chelation of Zn 2ϩ or genetic deletion of vesicular zinc transporter abrogated the privilege of MF inputs for LTP-IE induction. Moreover, the incompetence of somatic stimulation was rescued by the inhibition of PTP or a supplement of extracellular zinc, indicating that MF input-induced increase in dendritic [Zn 2ϩ ] facilitates the induction of LTP-IE by inhibiting PTP. Consistently, high-frequency MF stimulation induced immediate and delayed elevations of [Zn 2ϩ ] at proximal and distal dendrites, respectively. These results indicate that MF inputs are uniquely linked to the regulation of direct cortical inputs owing to synaptic Zn 2ϩ signaling.