Stress-induced changes of the cholinergic circuitry promote retrieval-based generalization of aversive memories.

Generalization, the process of applying knowledge acquired in one context to other contexts, often drives the expression of similar behaviors in related situations. At the cellular level, generalization is thought to depend on the activity of overlapping neurons that represent shared features between contexts (general representations). Using contextual fear conditioning in mice, we demonstrate that generalization can also occur in response to stress and result from reactivation of specific, rather than general context representations.

Stress-induced generalization of negative memories is mediated by an extended hippocampal circuit.

Memories of negative experiences exert important control of behavior in the face of actual or anticipated threat. Sometimes, however, this control extends to non-threatening situations, a phenomenon known as overgeneralization of negative memories. Overgeneralization is a reliable cognitive phenotype of major depressive disorder, generalized anxiety disorder, and post-traumatic stress disorder.

Primary cilia are required for the persistence of memory and stabilization of perineuronal nets.

It is well established that the formation of episodic memories requires multiple hippocampal mechanisms operating on different time scales. Early mechanisms of memory formation (synaptic consolidation) have been extensively characterized. However, delayed mechanisms, which maintain hippocampal activity as memories stabilize in cortical circuits, are not well understood.

Stress-related memories disrupt sociability and associated patterning of hippocampal activity: a role of hilar oxytocin receptor-positive interneurons.

In susceptible individuals, memories of stressful experiences can give rise to debilitating socio-affective symptoms. This occurs even when the ability to retrieve such memories is limited, as seen in patients suffering from traumatic amnesia. We therefore hypothesized that the encoding, rather than retrieval, mechanisms of stress-related memories underlie their impact on social and emotional behavior.

Excitatory VTA to DH projections provide a valence signal to memory circuits.

The positive or negative value (valence) of past experiences is normally integrated into neuronal circuits that encode episodic memories and plays an important role in guiding behavior. Here, we show, using mouse behavioral models, that glutamatergic afferents from the ventral tegmental area to the dorsal hippocampus (VTA→DH) signal negative valence to memory circuits, leading to the formation of fear-inducing context memories and to context-specific reinstatement of fear. To a lesser extent, these projections also contributed to opioid-induced place preference, suggesting a role in signaling positive valence as well, and thus a lack of dedicated polarity.

Differential Contributions of Glutamatergic Hippocampal→Retrosplenial Cortical Projections to the Formation and Persistence of Context Memories.

Learning to associate stressful events with specific environmental contexts depends on excitatory transmission in the hippocampus, but how this information is transmitted to the neocortex for lasting memory storage is unclear. We identified dorsal hippocampal (DH) projections to the retrosplenial cortex (RSC), which arise mainly from the subiculum and contain either the vesicular glutamate transporter 1 (vGlut1) or vGlut2. Both vGlut1+ and vGlut2+ axons strongly excite and disynaptically inhibit RSC pyramidal neurons in superficial layers, but vGlut2+ axons trigger greater inhibition that spreads to deep layers, indicating that these pathways engage RSC circuits via partially redundant, partially differentiated cellular mechanisms.

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory.

Understanding how episodic memories are formed and retrieved is necessary if we are to treat disorders in which they malfunction. Muscarinic acetylcholine receptors (mAChR) in the hippocampus and cortex underlie memory formation, but there is conflicting evidence regarding their role in memory retrieval. Additionally, there is no consensus on which mAChR subtypes are critical for memory processing.

GABAergic mechanisms regulated by miR-33 encode state-dependent fear.

Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar. Restricted access to such memories can present a risk for psychiatric disorders and hamper their treatment. To better understand the mechanisms underlying state-dependent fear, we used a mouse model of contextual fear conditioning.

Double Dissociation of the Roles of Metabotropic Glutamate Receptor 5 and Oxytocin Receptor in Discrete Social Behaviors.

Social interactions in vertebrates are complex phenomena based on affective and cognitive processes. Multiple brain regions and neurotransmitter systems are involved in the expression of social behaviors, but their individual roles in specific aspects of social interactions are not well understood. Here we investigated how Gq-protein-coupled metabotropic glutamate receptor 5 (mGluR5) and oxytocin receptor (Oxtr) affect social affiliation and social memory.

Role of oxytocin receptors in modulation of fear by social memory.

Rationale: Oxytocin receptors (Oxtr) are important mediators of social learning and emotion, with bidirectional effects on fear and anxiety. Contrary to the anxiolytic actions of Oxtr in the amygdala, we recently showed that Oxtr in the lateral septum mediate the enhancement of fear conditioning by social defeat in mice.

Objectives: Using positive social interactions, which impair fear conditioning, here we attempted to delineate whether the role of septal Oxtr in fear regulation depends on the valence of the social memory.

Fear-enhancing effects of septal oxytocin receptors.

The nonapeptide oxytocin is considered beneficial to mental health due to its anxiolytic, prosocial and antistress effects, but evidence for anxiogenic actions of oxytocin in humans has recently emerged. Using region-specific manipulations of the mouse oxytocin receptor (Oxtr) gene (Oxtr), we identified the lateral septum as the brain region mediating fear-enhancing effects of Oxtr. These effects emerge after social defeat and require Oxtr specifically coupled to the extracellular signal-regulated protein kinase pathway.

NMDA receptors in retrosplenial cortex are necessary for retrieval of recent and remote context fear memory.

Over time, memory retrieval is thought to transfer from the hippocampus to a distributed network of neocortical sites. Of these sites, the retrosplenial cortex (RSC) is robustly activated during retrieval of remotely acquired, emotionally valenced memories. It is unclear, however, whether RSC is specifically involved in memory storage or retrieval, and which neurotransmitter receptor mechanisms serve its function.

IQGAP1 regulates NR2A signaling, spine density, and cognitive processes.

General or brain-region-specific decreases in spine number or morphology accompany major neuropsychiatric disorders. It is unclear, however, whether changes in spine density are specific for an individual mental process or disorder and, if so, which molecules confer such specificity. Here we identify the scaffolding protein IQGAP1 as a key regulator of dendritic spine number with a specific role in cognitive but not emotional or motivational processes.

ERK-associated changes of AP-1 proteins during fear extinction.

Extensive research has unraveled the molecular basis of learning processes underlying contextual fear conditioning, but the mechanisms of fear extinction remain less known. Contextual fear extinction occurs when an aversive stimulus that initially caused fear is no longer present and depends on the activation of the extracellular signal-regulated kinase (ERK), among other molecules. Here we investigated how ERK signaling triggered by extinction affects its downstream targets belonging to the activator protein-1 (AP-1) transcription factor family.

Metabotropic glutamate receptor 5/Homer interactions underlie stress effects on fear.

Background: Glutamatergic transmission is one of the main components of the stress response; nevertheless, its role in the emotional stress sequelae is not known. Here, we investigated whether interactions between group I metabotropic glutamate receptors (metabotropic glutamate receptor 1 and metabotropic glutamate receptor 5 [mGluR5]) and Homer proteins mediate the delayed and persistent enhancement of fear induced by acute stress.

Methods: Antagonists and inverse agonists of metabotropic glutamate receptor 1 and mGluR5 were injected into the hippocampus after immobilization stress and before contextual fear conditioning.

Hippocampal NMDA receptor subunits differentially regulate fear memory formation and neuronal signal propagation.

Activation of NMDA receptors (NMDAR) in the hippocampus is essential for the formation of contextual and trace memory. However, the role of individual NMDAR subunits in the molecular mechanisms contributing to these memory processes is not known. Here we demonstrate, using intrahippocampal injection of subunit-selective compounds, that the NR2A-preferring antagonist impaired contextual and trace fear conditioning as well as learning-induced increase of the nuclear protein c-Fos.

Hippocampal Erk mechanisms linking prediction error to fear extinction: roles of shock expectancy and contextual aversive valence.

Extinction of fear requires learning that anticipated aversive events no longer occur. Animal models reveal that sustained phosphorylation of the extracellular signal-regulated kinase (Erk) in hippocampal CA1 neurons plays an important role in this process. However, the key signals triggering and regulating the activity of Erk are not known.

Segregated populations of hippocampal principal CA1 neurons mediating conditioning and extinction of contextual fear.

Learning processes mediating conditioning and extinction of contextual fear require activation of several key signaling pathways in the hippocampus. Principal hippocampal CA1 neurons respond to fear conditioning by a coordinated activation of multiple protein kinases and immediate early genes, such as cFos, enabling rapid and lasting consolidation of contextual fear memory. The extracellular signal-regulated kinase (Erk) additionally acts as a central mediator of fear extinction.