It has recently been shown that neurons in the lateral habenula (LHb), a nucleus that projects to midbrain reward areas, can signal negative reward or 'disappointment' by modulating a dopaminergic centre, and may be disrupted in depressive disorders. Experiments in rats exhibiting learned helplessness (a model of major depression) now show that excitatory synapses onto LHb neurons are potentiated, and that this correlates with helplessness behaviour. Depleting transmitter release by repeated electrical stimulation of the LHb using a protocol similar to deep brain stimulation rescues both synaptic changes and learned helplessness behaviour. These results point to a mechanism by which deep brain stimulation in LHb could be effective in treating depression. It has recently been shown that neurons in the lateral habenula (LHb), a nucleus that projects to midbrain reward areas, can signal aversive outcomes and may be disrupted in depressive disorders. This study now shows that in rats exhibiting learned helplessness (a model of major depression) excitatory synapses onto LHb neurons are potentiated, and that this correlates with helplessness behaviour. Furthermore, depleting transmitter release by repeated electrical stimulation of LHb using a protocol similar to deep brain stimulation rescues both synaptic changes and learned helplessness behaviour. The cellular basis of depressive disorders is poorly understood1. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome)2,3,4. LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA)2,5, that control reward-seeking behaviour6 and participate in depressive disorders7. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal’s helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed8,9, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

The authors show that fear conditioning induces potentiation of excitatory synapses onto somatostatin-positive inhibitory neurons in the lateral division of the central amygdala. Preventing this synaptic potentiation impairs the formation of fear memories, and activation of these neurons is necessary and sufficient for expression of fear memories. The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, the mechanism by which CeA contributes to the learning and expression of fear is unclear. We found that fear conditioning in mice induced robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of the CeA (CeL). This experience-dependent plasticity was cell specific, bidirectional and expressed presynaptically by inputs from the lateral amygdala. In particular, preventing synaptic potentiation onto somatostatin-positive neurons impaired fear memory formation. Furthermore, activation of these neurons was necessary for fear memory recall and was sufficient to drive fear responses. Our findings support a model in which fear conditioning–induced synaptic modifications in CeL favor the activation of somatostatin-positive neurons, which inhibit CeL output, thereby disinhibiting the medial subdivision of CeA and releasing fear expression.

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.

The changes in synaptic morphology and receptor content that underlie neural plasticity are poorly understood. Here, we use a pH-sensitive green fluorescent protein to tag recombinant glutamate receptors and monitor their dynamics onto dendritic spine surfaces. We show that chemically induced long-term potentiation (chemLTP) drives robust exocytosis of AMPA receptors. In contrast, the same stimulus produces a small reduction of NMDA receptors from the spine surface. chemLTP produces similar modification of small and large spines. Interestingly, during chemLTP induction, spines increase in volume before accumulation of AMPA receptors on their surface, indicating that distinct mechanisms underlie changes in morphology and receptor content.

In mice, glutamatergic globus pallidus neurons projecting to the lateral habenula (GPh neurons) bi-directionally encode positive and negative prediction error signals that are critical for outcome evaluation and are driven by a subset of basal ganglia circuits. The basal ganglia play a crucial role in action selection, but their involvement in evaluating the outcome of actions is less well understood. Bo Li and colleagues show that in mice, glutamatergic globus pallidus neurons projecting to the lateral habenula (GPh neurons) evaluate positive and negative action outcomes, thereby biasing subsequent actions, and this requires inhibitory and excitatory inputs to the GPh, respectively. Identifying the origin of these inputs in the striatum and the subthalamic nucleus, the authors propose that information about the selection and evaluation of actions is channelled through distinct, though intermingled, basal ganglia circuits. The basal ganglia, a group of subcortical nuclei, play a crucial role in decision-making by selecting actions and evaluating their outcomes1,2. While much is known about the function of the basal ganglia circuitry in selection1,3,4, how these nuclei contribute to outcome evaluation is less clear. Here we show that neurons in the habenula-projecting globus pallidus (GPh) in mice are essential for evaluating action outcomes and are regulated by a specific set of inputs from the basal ganglia. We find in a classical conditioning task that individual mouse GPh neurons bidirectionally encode whether an outcome is better or worse than expected. Mimicking these evaluation signals with optogenetic inhibition or excitation is sufficient to reinforce or discourage actions in a decision-making task. Moreover, cell-type-specific synaptic manipulations reveal that the inhibitory and excitatory inputs to the GPh are necessary for mice to appropriately evaluate positive and negative feedback, respectively. Finally, using rabies-virus-assisted monosynaptic tracing5, we show that the GPh is embedded in a basal ganglia circuit wherein it receives inhibitory input from both striosomal and matrix compartments of the striatum, and excitatory input from the ‘limbic’ regions of the subthalamic nucleus. Our results provide evidence that information about the selection and evaluation of actions is channelled through distinct sets of basal ganglia circuits, with the GPh representing a key locus in which information of opposing valence is integrated to determine whether action outcomes are better or worse than expected.