Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function.

Duplications and deletions of short chromosomal fragments are increasingly recognized as the cause for rare neurodevelopmental conditions and disorders. The gene encodes a protein kinase important for neuronal development and is part of a microduplication region on chromosome 12 that is associated with intellectual disabilities, autism, and epilepsy. We developed a conditional transgenic mouse with increased Ndr2 expression in postmigratory forebrain neurons to study the consequences of an increased gene dosage of this Hippo pathway kinase on brain circuitry and cognitive functions.

Regulation of CREB Phosphorylation in Nucleus Accumbens after Relief Conditioning.

Relief learning is the association of environmental cues with the cessation of aversive events. While there is increasing knowledge about the neural circuitry mediating relief learning, the respective molecular pathways are not known. Therefore, the aim of the present study was to examine different putative molecular pathways underlying relief learning.

Exploration of a novel virtual environment improves memory consolidation in ADHD.

Experimental evidence in rodents and humans suggests that long-term memory consolidation can be enhanced by the exploration of a novel environment presented during a vulnerable early phase of consolidation. This memory enhancing effect (behavioral tagging) is caused by dopaminergic and noradrenergic neuromodulation of hippocampal plasticity processes. In translation from animal to human research, we investigated whether behavioral tagging with novelty can be used to tackle memory problems observed in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).

Deficiency of the immunoproteasome subunit β5i/LMP7 supports the anxiogenic effects of mild stress and facilitates cued fear memory in mice.

Proteolysis as mediated by one of the major cellular protein degradation pathways, the ubiquitin-proteasome system (UPS), plays an essential role in learning and memory formation. However, the functional relevance of immunoproteasomes in the healthy brain and especially their impact on normal brain function including processes of learning and memory has not been investigated so far. In the present study, we analyzed the phenotypic effects of an impaired immunoproteasome formation using a β5i/LMP7-deficient mouse model in different behavioral paradigms focusing on locomotor activity, exploratory behavior, innate anxiety, startle response, prepulse inhibition, as well as fear and safety conditioning.

Intra-accumbal blockade of endocannabinoid CB1 receptors impairs learning but not retention of conditioned relief.

Humans and animals are able to associate an environmental cue with the feeling of relief from an aversive event, a phenomenon called relief learning. Relief from an aversive event is rewarding and a relief-associated cue later induces an attenuation of the startle magnitude or approach behavior. Previous studies demonstrated that the nucleus accumbens is essential for relief learning.

Relief learning requires a coincident activation of dopamine D1 and NMDA receptors within the nucleus accumbens.

Relief learning is the association of a stimulus with the offset of an aversive event. Later, the now conditioned relief stimulus induces appetitive-like behavioral changes. We previously demonstrated that the NMDA receptors within the nucleus accumbens (NAC) are involved in relief learning.

Relief memory consolidation requires protein synthesis within the nucleus accumbens.

Relief learning refers to the association of a stimulus with the relief from an aversive event. The thus-learned relief stimulus then can induce, e.g.

Relief learning is distinguished from safety learning by the requirement of the nucleus accumbens.

Aversive events induce aversive memories (fear learning) and can also establish appetitive memories. This is the case for cues associated with the cessation of an aversive event (relief learning) or occurring in an explicitly unpaired fashion (safety learning). However, the neural basis of relief and safety learning is poorly understood.

Circadian modulation of anxiety: a role for somatostatin in the amygdala.

Pharmacological evidence suggests that the neuropeptide somatostatin (SST) exerts anxiolytic action via the amygdala, but findings concerning the putative role of endogenous SST in the regulation of emotional responses are contradictory. We hypothesized that an endogenous regulation of SST expression over the course of the day may determine its function and tested both SST gene expression and the behavior of SST knock out (SST⁻/⁻) mice in different aversive tests in relation to circadian rhythm. In an open field and a light/dark avoidance test, SST⁻/⁻ mice showed significant hyperactivity and anxiety-like behavior during the second, but not during the first half of the active phase, failing to show the circadian modulation of behavior that was evident in their wild type littermates.

The GABA-synthetic enzyme GAD65 controls circadian activation of conditioned fear pathways.

Circadian fluctuations of fear and anxiety symptoms are observable in persons with post-traumatic stress disorder, generalized anxiety, and panic disorder; however, the underlying neurobiological mechanisms are not sufficiently understood. In the present study, we investigated the putative role of inhibitory neurotransmission in the circadian fluctuation of fear symptoms, using mice with genetic ablation of the γ-amino butyric acid (GABA) synthesizing isoenzyme, glutamic acid decarboxylase GAD65. We observed in these mutant mice an altered expression of conditioned fear with a profound reduction of freezing, and an increase of hyperactivity bouts occurring only when both fear conditioning training and retrieval testing were done at the beginning of their active phase.

Disruption of fear memory consolidation and reconsolidation by actin filament arrest in the basolateral amygdala.

The dynamic re-arrangement of actin filaments is an essential process in the plasticity of synaptic connections during memory formation. In this study, we determined in mice effects of actin filament arrest in the basolateral complex of the amygdala (BLA) at different time points after memory acquisition and re-activation, using the fungal cytotoxin phalloidin. Our data show a selective disruption of auditory cued but not contextual fear memory, when phalloidin was injected 6h after conditioning.

Deficiency of the 65 kDa isoform of glutamic acid decarboxylase impairs extinction of cued but not contextual fear memory.

Extinction procedures are clinically relevant for reducing pathological fear, and the mechanisms of fear regulation are a subject of intense research. The amygdala, hippocampus, and prefrontal cortex (PFC) have all been suggested to be key brain areas in extinction of conditioned fear. GABA has particularly been implicated in extinction learning, and the 65 kDa isoform of glutamic acid decarboxylase (GAD65) may be important in elevating GABA levels in response to environmental signals.

Role of the neural cell adhesion molecule (NCAM) in amygdalo-hippocampal interactions and salience determination of contextual fear memory.

Evidence suggests that the neural cell adhesion molecule (NCAM) is an important molecular constituent of adaptive and maladaptive circuit (re-)organization in the central nervous system. Here, we further investigate its putative involvement in amygdala and hippocampus functions during context fear memory formation. Using laser capture microdissection and quantitative RT-PCR, we show high NCAM mRNA expression levels in the lateral and basolateral subnuclei of the amygdala, as well as their training intensity- and context-dependent regulation during fear memory consolidation.

Identification of a neuropeptide S responsive circuitry shaping amygdala activity via the endopiriform nucleus.

Neuropeptide S (NPS) and its receptor are thought to define a set of specific brain circuits involved in fear and anxiety. Here we provide evidence for a novel, NPS-responsive circuit that shapes neural activity in the mouse basolateral amygdala (BLA) via the endopiriform nucleus (EPN). Using slice preparations, we demonstrate that NPS directly activates an inward current in 20% of EPN neurons and evokes an increase of glutamatergic excitation in this nucleus.

Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory.

Evidence suggests that plasticity of the amygdalar and hippocampal GABAergic system is critical for fear memory formation. In this study we investigated in wild-type and genetically manipulated mice the role of the activity-dependent 65-kDa isozyme of glutamic acid decarboxylase (GAD65) in the consolidation and generalization of conditioned fear. First, we demonstrate a transient reduction of GAD65 gene expression in the dorsal hippocampus (6 h post training) and in the basolateral complex of the amygdala (24 h post training) during distinct phases of fear memory consolidation.