Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats.

Purpose: Chemotherapy-related cognitive impairment (CRCI) is commonly reported following the administration of chemotherapeutic agents and comprises a wide variety of neurological problems. No effective treatments for CRCI are currently available. Here we examined the mechanisms involving cisplatin-induced hippocampal damage following cisplatin administration in a rat model and in cultured rat hippocampal neurons and neural stem/progenitor cells (NSCs).

Immediate-early gene transcriptional activation in hippocampus CA1 and CA3 does not accurately reflect rapid, pattern completion-based retrieval of context memory.

No studies to date have examined whether immediate-early gene (IEG) activation is driven by context memory recall. To address this question, we utilized the context preexposure facilitation effect (CPFE) paradigm. In CPFE, animals acquire contextual fear conditioning through hippocampus-dependent rapid retrieval of a previously formed contextual representation.

Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: Evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation.

Neuroinflammation is implicated in impairments in neuronal function and cognition that arise with aging, trauma, and/or disease. Therefore, understanding the underlying basis of the effect of immune system activation on neural function could lead to therapies for treating cognitive decline. Although neuroinflammation is widely thought to preferentially impair hippocampus-dependent memory, data on the effects of cytokines on cognition are mixed.

Retrieval-induced NMDA receptor-dependent Arc expression in two models of cocaine-cue memory.

The association of environmental cues with drugs of abuse results in persistent drug-cue memories. These memories contribute significantly to relapse among addicts. While conditioned place preference (CPP) is a well-established paradigm frequently used to examine the modulation of drug-cue memories, very few studies have used the non-preference-based model conditioned activity (CA) for this purpose.

Acute neuroinflammation impairs context discrimination memory and disrupts pattern separation processes in hippocampus.

Although it is known that immune system activation can impair cognition, no study to date has linked cognitive deficits during acute neuroinflammation to dysregulation of task-relevant neuronal ensemble activity. Here, we assessed both neural circuit activity and context discrimination memory retrieval, in a within-subjects design, of male rats given systemic administration of saline or lipopolysaccharide (LPS). Rats were exposed over several days to two similar contexts: one of which was paired with weak foot shock and the other was not.

Temporal dynamics of Arc gene induction in hippocampus: relationship to context memory formation.

Past studies have proposed a role for the hippocampus in the rapid encoding of context memories. Despite this, there is little data regarding the molecular processes underlying the stable formation of a context representation that occurs in the time window established through such behavioral studies. One task that is useful for investigating the rapid encoding of context is contextual fear conditioning (CFC).

Loss of activity-dependent Arc gene expression in the retrosplenial cortex after hippocampal inactivation: interaction in a higher-order memory circuit.

The rodent hippocampus is well known for its role in spatial navigation and memory, and recent evidence points to the retrosplenial cortex (RSC) as another element of a higher order spatial and mnemonic circuit. However, the functional interplay between hippocampus and RSC during spatial navigation remains poorly understood. To investigate this interaction, we examined cell activity in the RSC during spatial navigation in the water maze before and after acute hippocampal inactivation using expression of two immediate-early genes (IEGs), Arc and Homer 1a (H1a).

Rapid activation of plasticity-associated gene transcription in hippocampal neurons provides a mechanism for encoding of one-trial experience.

The hippocampus is hypothesized to support rapid encoding of ongoing experience. A critical prerequisite for such function is the ability to readily recruit enduring synaptic plasticity in hippocampal neurons. Hippocampal long-term potentiation (LTP) and memory consolidation require expression of the immediate-early gene (IEG) Arc.

The immediate early gene arc/arg3.1: regulation, mechanisms, and function.

In a manner unique among activity-regulated immediate early genes (IEGs), mRNA encoded by Arc (also known as Arg3.1) undergoes rapid transport to dendrites and local synaptic translation. Despite this intrinsic appeal, relatively little is known about the neuronal and behavioral functions of Arc or its molecular mechanisms of action.

Using immediate-early genes to map hippocampal subregional functions.

Different functions have been suggested for the hippocampus and its subdivisions along both transversal and longitudinal axes. Expression of immediate-early genes (IEGs) has been used to map specific functions onto neuronal activity in different areas of the brain including the hippocampus (IEG imaging). Here we review IEG studies on hippocampal functional dissociations with a particular focus on the CA3 subregion.

Networks of neurons, networks of genes: an integrated view of memory consolidation.

Investigations into the mechanisms of memory formation have abided by the central tenet of the consolidation theory-that memory formation occurs in stages which differ in their requirement for protein synthesis. The current most widely accepted hypothesis posits that new memories are encoded as neural activity-induced changes in synaptic efficacy, and stabilization of these changes requires de novo protein synthesis. However, the basic assumptions of this view have been challenged by concerns regarding the specificity of the effects of the protein synthesis inhibitors used to support the claim.

A multi-model approach to simultaneous segmentation and classification of heterogeneous populations of cell nuclei in 3D confocal microscope images.

Automated segmentation and morphometry of fluorescently labeled cell nuclei in batches of 3D confocal stacks is essential for quantitative studies. Model-based segmentation algorithms are attractive due to their robustness. Previous methods incorporated a single nuclear model.

A form of perforant path LTP can occur without ERK1/2 phosphorylation or immediate early gene induction.

Stimulation paradigms that induce perforant path long-term potentiation (LTP) initiate phosphorylation of ERK1/2 and induce expression of a variety of immediate early genes (IEGs). These events are thought to be critical components of the mechanism for establishing the changes in synaptic efficacy that endure for hours or longer. Here we show that in mice, perforant path LTP can be induced using a standard protocol (repeated trains at 250 Hz), without accompanying increases in immunostaining for p-ERK1/2 or increased in expression of representative IEGs (Arc and c-fos).

Neuronal competition and selection during memory formation.

Competition between neurons is necessary for refining neural circuits during development and may be important for selecting the neurons that participate in encoding memories in the adult brain. To examine neuronal competition during memory formation, we conducted experiments with mice in which we manipulated the function of CREB (adenosine 3',5'-monophosphate response element-binding protein) in subsets of neurons. Changes in CREB function influenced the probability that individual lateral amygdala neurons were recruited into a fear memory trace.

Selective cholinergic depletion of the hippocampus spares both behaviorally induced Arc transcription and spatial learning and memory.

We demonstrated previously that when hippocampal-dependent learning and plasticity are compromised by fornix lesions, behaviorally induced expression of the immediate early gene, Arc, is correspondingly low. The medial septum and the vertical diagonal band are major sources of subcortical afferents that innervate the hippocampus via the fornix. Here we assessed the specific contribution of cholinergic afferents from these regions to the impairments in spatial learning and behavioral induction of Arc transcription produced by fornix lesions.

Advanced imaging of multiple mRNAs in brain tissue using a custom hyperspectral imager and multivariate curve resolution.

Simultaneous imaging of multiple cellular components is of tremendous importance in the study of complex biological systems, but the inability to use probes with similar emission spectra and the time consuming nature of collecting images on a confocal microscope are prohibitive. Hyperspectral imaging technology, originally developed for remote sensing applications, has been adapted to measure multiple genes in complex biological tissues. A spectral imaging microscope was used to acquire overlapping fluorescence emissions from specific mRNAs in brain tissue by scanning the samples using a single fluorescence excitation wavelength.

Spatial exploration induces ARC, a plasticity-related immediate-early gene, only in calcium/calmodulin-dependent protein kinase II-positive principal excitatory and inhibitory neurons of the rat forebrain.

Active behavior, such as exploring a novel environment, induces the expression of the immediate-early gene Arc (activity-regulated cytoskeletal associated protein, or Arg 3.1) in many brain regions, including the hippocampus, neocortex, and striatum. Arc messenger ribonucleic acid and protein are localized in activated dendrites, and Arc protein is required for the maintenance of long-term potentiation and memory consolidation.

Expression and function of SNAP-25 as a universal SNARE component in GABAergic neurons.

Intracellular vesicular trafficking and membrane fusion are important processes for nervous system development and for the function of neural circuits. Synaptosomal-associated protein 25 kDa (SNAP-25) is a component of neural soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) core complexes that mediate the exocytotic release of neurotransmitters at chemical synapses. Previous results from mouse mutant models and pharmacological/neurotoxin blockades have demonstrated a critical role for SNAP-25-containing SNARE complexes in action potential (AP)-dependent release at cholinergic and glutamatergic synapses and for calcium-triggered catecholamine release from chromaffin cells.

Recent behavioral history modifies coupling between cell activity and Arc gene transcription in hippocampal CA1 neurons.

The ability of neurons to alter their transcriptional programs in response to synaptic input is of fundamental importance to the neuroplastic mechanisms underlying learning and memory. Because of technical limitations of conventional gene detection methods, the current view of activity-dependent neural transcription derives from experiments in which neurons are assumed quiescent until a signaling stimulus is given. The present study was designed to move beyond this static model by examining how earlier episodes of neural activity influence transcription of the immediate-early gene Arc.

Mapping behaviorally relevant neural circuits with immediate-early gene expression.

Immediate-early genes have gained widespread popularity as activity markers for mapping neuronal circuits involved in specific behaviors in many different species. In situ immediate early gene detection methods provide cellular level resolution, a major benefit for mapping neuronal networks. Recent advances using fluorescence in situ hybridization also afford temporal resolution, enabling within-animal activity maps for two distinct behaviors.

Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus.

Activation of beta-adrenoceptors in the basolateral complex of the amygdala (BLA) modulates memory storage processes and long-term potentiation in downstream targets of BLA efferents, including the hippocampus. Here, we show that this activation also increases hippocampal levels of activity-regulated cytoskeletal protein (Arc), an immediate-early gene (also termed Arg 3.1) implicated in hippocampal synaptic plasticity and memory consolidation processes.

Mapping neuronal activation and the influence of adrenergic signaling during contextual memory retrieval.

We recently described a critical role for adrenergic signaling in the hippocampus during contextual and spatial memory retrieval. To determine which neurons are activated by contextual memory retrieval and its sequelae in the presence and absence of adrenergic signaling, transcriptional imaging for the immediate-early gene Arc was used in control and mutant mice lacking norepinephrine and epinephrine. This imaging approach permits the identification of neuronal genomic activation specific to one of two behavioral epochs in the same animal.

Hierarchical, model-based merging of multiple fragments for improved three-dimensional segmentation of nuclei.

Background: Automated segmentation of fluorescently labeled cell nuclei in three-dimensional confocal images is essential for numerous studies, e.g., spatiotemporal fluorescence in situ hybridization quantification of immediate early gene transcription.

Ensemble dynamics of hippocampal regions CA3 and CA1.

Computational models based on hippocampal connectivity have proposed that CA3 is uniquely positioned as an autoassociative memory network, capable of performing the competing functions of pattern completion and pattern separation. Recently, three independent studies, two using parallel neurophysiological recording methods and one using immediate-early gene imaging, have examined the responses of CA3 and CA1 ensembles to alterations of environmental context in rats. The results provide converging evidence that CA3 is capable of performing nonlinear transformations of sensory input patterns, whereas CA1 may represent changes in input in a more linear fashion.