Natalie C. Tronson

Molecular mechanisms of memory reconsolidation

Memory reconsolidation has been argued to be a distinct process that serves to maintain, strengthen or modify memories. Specifically, the retrieval of a previously consolidated memory has been hypothesized to induce an additional activity-dependent labile period during which the memory can be modified. Understanding the molecular mechanisms of reconsolidation could provide crucial insights into the dynamic aspects of normal mnemonic function and psychiatric disorders that are characterized by exceptionally strong and salient emotional memories.

Bidirectional behavioral plasticity of memory reconsolidation depends on amygdalar protein kinase A

Reconsolidation—the stabilization of a memory after retrieval—is hypothesized to be a critical and distinct component of memory processing, the disruption of which results in memory impairment. In the rat, we found that activation of amygdalar protein kinase A (PKA) was sufficient to enhance memory only when it was retrieved; in contrast, PKA inhibition impaired reconsolidation. This study demonstrates both a selective enhancement and an impairment of memory reconsolidation dependent on amygdalar PKA.

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.

ΔFosB in the Nucleus Accumbens Regulates Food-Reinforced Instrumental Behavior and Motivation

Alterations in motivation have been implicated in the pathophysiology of several psychiatric disorders, including substance abuse and depression. Repeated exposure to drugs of abuse or stress is known to persistently induce the transcription factor ΔFosB in the nucleus accumbens (NAc) and dorsal striatum, effects hypothesized to contribute to neuroadaptations in dopamine-regulated signaling. Little is known, however, about the specific involvement of ΔFosB in dysregulation of appetitively motivated behaviors. We show here that inducible overexpression of ΔFosB in NAc and dorsal striatum of bitransgenic mice, or specifically in the NAc core of rats by use of viral-mediated gene transfer, enhanced food-reinforced instrumental performance and progressive ratio responding. Very similar behavioral effects were found after previous repeated exposure to cocaine, amphetamine, MDMA [(+)-3,4-methylenedioxymethamphetamine], or nicotine in rats. These results reveal the powerful regulation of motivational processes by ΔFosB, and provide evidence that drug-induced alterations in gene expression via induction of ΔFosB within the NAc core may play a critical role in the impact of motivational influences on instrumental behavior.

The Striatal-Enriched Protein Tyrosine Phosphatase Gates Long-Term Potentiation and Fear Memory in the Lateral Amygdala

BACKGROUND Formation of long-term memories is critically dependent on extracellular-regulated kinase (ERK) signaling. Activation of the ERK pathway by the sequential recruitment of mitogen-activated protein kinases is well understood. In contrast, the proteins that inactivate this pathway are not as well characterized. METHODS Here we tested the hypothesis that the brain-specific striatal-enriched protein tyrosine phosphatase (STEP) plays a key role in neuroplasticity and fear memory formation by its ability to regulate ERK1/2 activation. RESULTS STEP co-localizes with the ERKs within neurons of the lateral amygdala. A substrate-trapping STEP protein binds to the ERKs and prevents their nuclear translocation after glutamate stimulation in primary cell cultures. Administration of TAT-STEP into the lateral amygdala (LA) disrupts long-term potentiation (LTP) and selectively disrupts fear memory consolidation. Fear conditioning induces a biphasic activation of ERK1/2 in the LA with an initial activation within 5 minutes of training, a return to baseline levels by 15 minutes, and an increase again at 1 hour. In addition, fear conditioning results in the de novo translation of STEP. Inhibitors of ERK1/2 activation or of protein translation block the synthesis of STEP within the LA after fear conditioning. CONCLUSIONS Together, these data imply a role for STEP in experience-dependent plasticity and suggest that STEP modulates the activation of ERK1/2 during amygdala-dependent memory formation. The regulation of emotional memory by modulating STEP activity may represent a target for the treatment of psychiatric disorders such as posttraumatic stress disorder (PTSD), panic, and anxiety disorders.

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. We addressed these questions by inhibiting NMDARs in RSC via infusions of APV before tests for context fear in mice. Anterior cingulate cortex (ACC) and dorsal hippocampus (DH), which have been implicated in the retrieval of remote and recent memory, respectively, served as neuroanatomical controls. Surprisingly, infusion of APV only into RSC, but not ACC or DH, abolished retrieval of remote memory, as revealed by lack of freezing to the conditioning context. APV infused into RSC also impaired retrieval of recent memory, but had no effect on conditioning or memory storage. Within-subject experiments confirmed that the role of RSC in memory retrieval is not time limited. RSC-dependent context fear memory retrieval was mediated by NR2A, but not NR2B, subunit-containing NMDARs. Collectively, these data are the first demonstration that NMDARs in RSC are necessary for the retrieval of remote and recent memories of fear-evoking contexts. Dysfunction of RSC may thereby contribute significantly to the reexperiencing of traumatic memories in patients with posttraumatic stress disorder.

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. It is not known however, whether these molecular events take place in overlapping or nonoverlapping neuronal populations. By using mouse models of conditioning and extinction of fear, we set out to determine the time course of cFos and Erk activity, their cellular overlap, and regulation by afferent cholinergic input from the medial septum. Analyses of cFos+ and pErk+ cells by immunofluorescence revealed predominant nuclear activation of either protein during conditioning and extinction of fear, respectively. Transgenic cFos-LacZ mice were further used to label in vivo Fos+ hippocampal cells during conditioning followed by pErk immunostaining after extinction. The results showed that these signaling molecules were activated in segregated populations of hippocampal principal neurons. Furthermore, immunotoxin-induced lesions of medial septal neurons, providing cholinergic input into the hippocampus, selectively abolished Erk activation and extinction of fear without affecting cFos responses and conditioning. These results demonstrate that extinction mechanisms based on Erk signaling involve a specific population of CA1 principal neurons distinctively regulated by afferent cholinergic input from the medial septum.

Modulation of learning and memory by cytokines: Signaling mechanisms and long term consequences

This review describes the role of cytokines and their downstream signaling cascades on the modulation of learning and memory. Immune proteins are required for many key neural processes and dysregulation of these functions by systemic inflammation can result in impairments of memory that persist long after the resolution of inflammation. Recent research has demonstrated that manipulations of individual cytokines can modulate learning, memory, and synaptic plasticity. The many conflicting findings, however, have prevented a clear understanding of the precise role of cytokines in memory. Given the complexity of inflammatory signaling, understanding its modulatory role requires a shift in focus from single cytokines to a network of cytokine interactions and elucidation of the cytokine-dependent intracellular signaling cascades. Finally, we propose that whereas signal transduction and transcription may mediate short-term modulation of memory, long-lasting cellular and molecular mechanisms such as epigenetic modifications and altered neurogenesis may be required for the long lasting impact of inflammation on memory and cognition.

N-CADHERIN REGULATES CYTOSKELETALLY-ASSOCIATED IQGAP1/ERK SIGNALING AND MEMORY FORMATION

Cadherin-mediated interactions are integral to synapse formation and potentiation. Here we show that N-cadherin is required for memory formation and regulation of a subset of underlying biochemical processes. N-cadherin antagonistic peptide containing the His-Ala-Val motif (HAV-N) transiently disrupted hippocampal N-cadherin dimerization and impaired the formation of long-term contextual fear memory while sparing short-term memory, retrieval, and extinction. HAV-N impaired the learning-induced phosphorylation of a distinctive, cytoskeletally associated fraction of hippocampal Erk-1/2 and altered the distribution of IQGAP1, a scaffold protein linking cadherin-mediated cell adhesion to the cytoskeleton. This effect was accompanied by reduction of N-cadherin/IQGAP1/Erk-2 interactions. Similarly, in primary neuronal cultures, HAV-N prevented NMDA-induced dendritic Erk-1/2 phosphorylation and caused relocation of IQGAP1 from dendritic spines into the shafts. The data suggest that the newly identified role of hippocampal N-cadherin in memory consolidation may be mediated, at least in part, by cytoskeletal IQGAP1/Erk signaling.

Molecular Specificity of Multiple Hippocampal Processes Governing Fear Extinction

Over many years, fear extinction has been conceptualized as one dominant process, new inhibitory learning, which serves to dampen previously acquired fear. Here we present an alternative view, that brain region-specific processing of representations, expectations and emotional attributes of the fear-provoking event, recruits unique mechanisms that interdependently contribute to the conditioning and extinction of fear. The co-occurrence of these mechanisms within the fear circuit can thus be tracked and differentiated at a molecular and cellular level. Among others, the transcriptional regulators cFos, cAMP-dependent response element binding protein (CREB), Zif268, and extracellular signal-regulated kinases (Erk) stand out as hippocampal nuclear markers signaling novelty, arousal, retrieval, and prediction error, respectively. Consistent with evidence from human studies, these findings indicate that, beyond inhibitory learning, fear extinction requires modification of the emotional attributes and expectations that define the threatening context. Given the likely dysregulation of one or more of these processes in anxiety disorders, a key research challenge for the future is the identification and enhancement of individual extinction mechanisms to target the specific components of fear. Environmental stimuli lacking affective properties (conditioned stimuli, CS) rapidly become threatening if presented with stressful events (unconditioned stimuli, US). Consequently, based on a CS-US association, the presentation of the CS triggers species-specific fear responses until the US consistently stops occurring. At that point, new learning takes place and the fear response declines, a phenomenon termed extinction. The view that extinction occurs because a new, inhibitory CS-noUS association gains control over behavior, has remained dominant in the field. The implications of impaired fear regulation in the development of anxiety disorders have stimulated intense research in this area. Rodent studies identified the circuits involved in the conditioning and extinction of fear of salient cues, generating data that were confirmed in humans with brain imaging approaches. Nevertheless, research with experimental animals has not fully taken advantage of human data in order to better interpret extinction mechanisms in the framework of learning, expectation and emotion governing fear-motivated behavior. The present article aims to summarize recent molecular evidence on fear extinction, focusing on hippocampal mechanisms and experimental models of contextual fear, and compare the results with other relevant fear paradigms and human imaging studies. Instead of conceptualizing extinction learning as one process, such as CS-noUS association or inhibitory learning, we propose that fear extinction reflects the behavioral output of several region-specific learning processes that modify different components of the conditioning memory. The significance of these findings is discussed in the framework of fear regulation and anxiety disorders.