Inhibiting projections from the paraventricular nucleus of the thalamus to a specific division of the amygdala prevents fear conditioning in mice, indicating an important role for the thalamus–amygdala circuit in establishing and maintaining fear responses. Fear association memories are thought to be stored in the amygdala and are accessible throughout the lifetime of an animal. However, the circuits required for retrieval of this memory at different times are still unknown. Recent work revealed that the paraventricular nucleus of the thalamus (PVT) is strongly activated following physical and psychological stress in mice, and now two papers published in this week's issue of Nature demonstrate a role for the PVT as a critical memory/retrieval node in the thalamus during the transition from short-term to long-term storage of fear association memories. Mario Penzo et al. show that inhibiting projections from the PVT to a specific division of the amygdala prevented fear conditioning via disruption of the typical fear-induced synaptic potentiation on a specific subset of interneurons found in the amygdala following behavioural fear training. Fabricio Do-Monte et al. dissociate early from late retrieval time points and demonstrate that while the PVT is critical for late-time-point fear-memory retrieval, a separate circuit originating from the prelimbic prefrontal cortex and projecting to the amygdala is critical only for early-time-point retrieval. Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors1,2,3. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression4,5. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM+) CeL neurons, which has previously been shown to store fear memory6. Consistently, we found that PVT neurons preferentially innervate SOM+ neurons in the CeL, and stimulation of PVT afferents facilitated SOM+ neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression5,6. Notably, PVT modulation of SOM+ CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM+ CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT–CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.

System x_c⁻exchanges intracellular glutamate for extracellular cystine, giving it a potential role in intracellular glutathione synthesis and nonvesicular glutamate release. We report that mice lacking the specific xCT subunit of system x_c⁻(xCT^−/−) do not have a lower hippocampal glutathione content, increased oxidative stress or brain atrophy, nor exacerbated spatial reference memory deficits with aging. Together these results indicate that loss of system x_c⁻does not induce oxidative stressin vivo. YoungxCT^−/−mice did however display a spatial working memory deficit. Interestingly, we observed significantly lower extracellular hippocampal glutamate concentrations inxCT^−/−mice compared to wild-type littermates. Moreover, intrahippocampal perfusion with system x_c⁻inhibitors lowered extracellular glutamate, whereas the system x_c⁻activatorN-acetylcysteine elevated extracellular glutamate in the rat hippocampus. This indicates that system x_c⁻may be an interesting target for pathologies associated with excessive extracellular glutamate release in the hippocampus. Correspondingly, xCT deletion in mice elevated the threshold for limbic seizures and abolished the proconvulsive effects ofN-acetylcysteine. These novel findings sustain that system x_c⁻is an important source of extracellular glutamate in the hippocampus. System x_c⁻is required for optimal spatial working memory, but its inactivation is clearly beneficial to decrease susceptibility for limbic epileptic seizures.

The striatum projection neurons are striatonigral and striatopallidal medium sized-spiny neurons (MSNs) that preferentially express D1 (D1R) and D2 (D2R) dopamine receptors, respectively. It is generally assumed that these neurons are physically intermingled, without cytoarchitectural organization although this has not been tested. To address this question we used BAC transgenic mice expressing enhanced green fluorescence (EGFP) under the control of Drd1a or Drd2 promoter and spatial point pattern statistics. We demonstrate that D1R- and D2R-expressing MSNs are randomly distributed in most of the dorsal striatum, whereas a specific region in the caudal striatum, adjacent to the GPe, appears to lack neurons expressing markers for indirect pathway neurons. This area comprises almost exclusively D1R-expressing MSNs. These neurons receive excitatory inputs from the primary auditory cortex and the medial geniculate thalamic nucleus and a rich dopamine innervation. This area contains cholinergic and GABAergic interneurons but apparently no D2R/A2aR modulation because no fluorescence was detected in the neuropil in Drd2-EGFP, Drd2-Cre and Adora-Cre BAC reporter mice. This striatal area that expresses calbindin-D28K, VGluT1 and 2, is poor in µ opiate receptors and preproenkephalin. Altogether, the differences observed in D1R-MSNs, D2R-MSNs and interneurons densities, as well as the anatomical segregation of D1R- and D2R/A2aR-expressing MSNs suggest that there are regional differences in the organization of the striatum.

Significance: Higher-level cognitive processes strongly depend on a complex interplay between the mediodorsal thalamus and the prefrontal cortex. Alteration of thalamofrontal connectivity has been involved in schizophrenia. Prefrontal serotonin (5-HT)_2Areceptors play an essential role in cortical network activity but the mechanism underlying their modulation of synaptic plasticity remains unexplored. Here, we demonstrate—to our knowledge for the first time—a physiological role of presynaptic 5-HT_2Areceptors in the NMDA-operated induction of temporal-dependent plasticity at thalamocortical synapses. We show that 5-HT_2A^−/−mice exhibit alterations in plasticity and associative memory that are rescued by re-expressing receptors in the thalamus. These findings highlight a critical role of presynaptic 5-HT_2Areceptor dysfunction in cognitive symptoms observed in schizophrenia.