Cognitive Flexibility Is Selectively Impaired by Radiation and Is Associated with Differential Recruitment of Adult-Born Neurons.

Exposure to elevated doses of ionizing radiation, such as those in therapeutic procedures, catastrophic accidents, or space exploration, increases the risk of cognitive dysfunction. The full range of radiation-induced cognitive deficits is unknown, partly because commonly used tests may be insufficiently sensitive or may not be adequately tuned for assessing the fine behavioral features affected by radiation. Here, we asked whether γ-radiation might affect learning, memory, and the overall ability to adapt behavior to cope with a challenging environment (cognitive/behavioral flexibility). We developed a new behavioral assay, the context discrimination Morris water maze (cdMWM) task, which is hippocampus-dependent and requires the integration of various contextual cues and the adjustment of search strategies. We exposed male mice to 1 or 5 Gy of γ rays and, at different time points after irradiation, trained them consecutively in spatial MWM, reversal MWM, and cdMWM tasks, and assessed their learning, navigational search strategies, and memory. Mice exposed to 5 Gy performed successfully in the spatial and reversal MWM tasks; however, in the cdMWM task 6 or 8 weeks (but not 3 weeks) after irradiation, they demonstrated transient learning deficit, decreased use of efficient spatially precise search strategies during learning, and, 6 weeks after irradiation, memory deficit. We also observed impaired neurogenesis after irradiation and selective activation of 12-week-old newborn neurons by specific components of cdMWM training paradigm. Thus, our new behavioral paradigm reveals the effects of γ-radiation on cognitive flexibility and indicates an extended timeframe for the functional maturation of new hippocampal neurons.SIGNIFICANCE STATEMENT Exposure to radiation can affect cognitive performance and cognitive flexibility - the ability to adapt to changed circumstances and demands. The full range of consequences of irradiation on cognitive flexibility is unknown, partly because of a lack of suitable models. Here, we developed a new behavioral task requiring mice to combine various types of cues and strategies to find a correct solution. We show that animals exposed to γ-radiation, despite being able to successfully solve standard problems, show delayed learning, deficient memory, and diminished use of efficient navigation patterns in circumstances requiring adjustments of previously used search strategies. This new task could be applied in other settings for assessing the cognitive changes induced by aging, trauma, or disease.

Multisession Anodal Transcranial Direct Current Stimulation Enhances Adult Hippocampal Neurogenesis and Context Discrimination in Mice.

Transcranial direct current stimulation (tDCS) is a promising noninvasive neuromodulatory treatment option for multiple neurologic and psychiatric disorders, but its mechanism of action is still poorly understood. Adult hippocampal neurogenesis (AHN) continues throughout life and is crucial for preserving several aspects of hippocampal-dependent cognitive functions. Nevertheless, the contribution of AHN in the neuromodulatory effects of tDCS remains unexplored. Here, we sought to investigate whether multisession anodal tDCS may modulate AHN and its associated cognitive functions. Multisession anodal tDCS were applied on the skull over the hippocampus of adult male mice for 20 min at 0.25 mA once daily for 10 d totally. We found that multisession anodal tDCS enhances AHN by increasing the proliferation, differentiation and survival of neural stem/progenitor cells (NSPCs). In addition, tDCS treatment increased cell cycle reentry and reduced cell cycle exit of NSPCs. The tDCS-treated mice exhibited a reduced GABAergic inhibitory tone in the dentate gyrus compared with sham-treated mice. The effect of tDCS on the proliferation of NSPCs was blocked by pharmacological restoration of GABAB receptor-mediated inhibition. Functionally, multisession anodal tDCS enhances performance on a contextual fear discrimination task, and this enhancement was prevented by blocking AHN using the DNA alkylating agent temozolomide (TMZ). Our results emphasize an important role for AHN in mediating the beneficial effects of tDCS on cognitive functions that substantially broadens the mechanistic understanding of tDCS beyond its well-described in hippocampal synaptic plasticity.SIGNIFICANCE STATEMENT Transcranial direct current stimulation (tDCS) has been shown to effectively enhance cognitive functions in healthy and pathologic conditions. However, the mechanisms underlying its effects are largely unknown and need to be better understood to enable its optimal clinical use. This study shows that multisession anodal tDCS enhances adult hippocampal neurogenesis (AHN) and therefore contributes to enhance context discrimination in mice. Our results also show that the effect of tDCS on AHN is associated with reduced GABAergic inhibition in the dentate gyrus. Our study uncovers a novel mechanism of anodal tDCS to elicit cognitive-enhancing effects and may have the potential to improve cognitive decline associated with normal aging and neurodegenerative disorders.

Appetitive and aversive sensory preconditioning in rats is impaired by disruption of the postrhinal cortex.

Episodic memory involves binding stimuli and/or events together in time and place. Furthermore, memories become more complex when new experiences influence the meaning of stimuli within the original memory. Thus collectively, complex episodic memory formation and maintenance involves processes such as encoding, storage, retrieval, updating and reconsolidation, which can be studied using animal models of higher-order conditioning. In the present study aversive and appetitive sensory preconditioning paradigms were used to test the hypothesis that the postrhinal cortex (POR), which is a component of the hippocampal memory system, is involved in higher-order conditioning. Drawing on the known role of the POR in contextual learning, Experiment 1 employed a four-phase sensory preconditioning task that involved fear learning and context discrimination in rats with or without permanent lesions of the POR. In parallel, to examine POR function during higher-order conditioning in the absence of a particular spatial arrangement, Experiments 2 and 3 used a three-phase sensory preconditioning paradigm involving phasic stimuli. In Experiment 2, bilateral lesions of the POR were made and in Experiment 3, a chemogenetic approach was used to temporarily inactivate POR neurons during each phase of the paradigm. Evidence of successful sensory preconditioning was observed in sham rats which, during the critical context discrimination test, demonstrated higher levels of freezing behavior when re-exposed to the paired versus the unpaired context, whereas POR-lesioned rats did not. Data from the appetitive sensory preconditioning paradigm also confirmed the hypothesis in that during the critical auditory discrimination test, sham rats showed greater food cup responding following presentations of the paired compared to the unpaired auditory stimulus, whereas POR-lesioned rats did not. Lastly, in Experiment 3, when the POR was inactivated only during preconditioning or only during conditioning, discrimination during the critical auditory test was impaired. Thus, regardless of whether stimulus-stimulus associations were formed between static or phasic stimuli or whether revaluation of the paired stimulus occurred through association with an aversive or an appetitive unconditioned stimulus, the effects were the same; POR lesions disrupted the ability to use higher-order conditioned stimuli to guide prospective behavior.

Putting fear in context: Elucidating the role of the retrosplenial cortex in context discrimination in rats.

The retrosplenial cortex (RSC), which receives visuo-spatial sensory input and interacts with numerous hippocampal memory system structures, has a well-established role in contextual learning and memory. While it has been demonstrated that RSC function is necessary to learn to recognize a single environment that is directly paired with an aversive event, the role of the RSC in discriminating between two different contexts remains largely unknown. To address this, first order (Experiment 1) and higher order (Experiment 2) fear conditioning paradigms were conducted with sham and RSC-lesioned rats. In Experiment 1 rats were exposed to one context in which shock was delivered and to a second, distinct context without shock. Their ability to discriminate between the contexts was assessed during a re-exposure test. In a second experiment, a new cohort of RSC-lesioned rats was exposed to two contexts made distinct through visual, olfactory and auditory stimuli. In a subsequent conditioning phase, the salience of one of the auditory stimuli was paired to an aversive footshock while the other was not. Similar to Experiment 1, freezing behavior was analyzed upon re-exposure to the contexts in the absence of both the auditory cue and the footshock. The results revealed that RSC is not necessary for rats to use contextual information to successfully discriminate between two contexts under the relatively simple demands involved in this first order conditioning paradigm but that context discrimination is impaired when the processing of complex and/or ambiguous contextual stimuli is required to select appropriate behavioral responses.

Hippocampal damage causes retrograde but not anterograde memory loss for context fear discrimination in rats.

There is a substantial body of evidence that the hippocampus (HPC) plays and essential role in context discrimination in rodents. Studies reporting anterograde amnesia (AA) used repeated, alternating, distributed conditioning and extinction sessions to measure context fear discrimination. In addition, there is uncertainty about the extent of damage to the HPC. Here, we induced conditioned fear prior to discrimination tests and rats sustained extensive, quantified pre- or post-training HPC damage. Unlike previous work, we found that extensive HPC damage spares context discrimination, we observed no AA. There must be a non-HPC system that can acquire long-term memories that support context fear discrimination. Post-training HPC damage caused retrograde amnesia (RA) for context discrimination, even when rats are fear conditioned for multiple sessions. We discuss the implications of these findings for understanding the role of HPC in long-term memory.

Place field repetition and spatial learning in a multicompartment environment.

Recent studies have shown that place cells in the hippocampus possess firing fields that repeat in physically similar, parallel environments. These results imply that it should be difficult for animals to distinguish parallel environments at a behavioral level. To test this, we trained rats on a novel odor-location task in an environment with four parallel compartments which had previously been shown to yield place field repetition. A second group of animals was trained on the same task, but with the compartments arranged in different directions, an arrangement we hypothesised would yield less place field repetition. Learning of the odor-location task in the parallel compartments was significantly impaired relative to learning in the radially arranged compartments. Fewer animals acquired the full discrimination in the parallel compartments compared to those trained in the radial compartments, and the former also required many more sessions to reach criterion compared to the latter. To confirm that the arrangement of compartments yielded differences in place cell repetition, in a separate group of animals we recorded from CA1 place cells in both environments. We found that CA1 place cells exhibited repeated fields across four parallel local compartments, but did not do so when the same compartments were arranged radially. To confirm that the differences in place field repetition across the parallel and radial compartments depended on their angular arrangement, and not incidental differences in access to an extra-maze visual landmark, we repeated the recordings in a second set of rats in the absence of the orientation landmark. We found, once again, that place fields showed repetition in parallel compartments, and did not do so in radially arranged compartments. Thus place field repetition, or lack thereof, in these compartments was not dependent on extra-maze cues. Together, these results imply that place field repetition constrains spatial learning.

The dynamic impact of repeated stress on the hippocampal spatial map.

Stress alters the function of many physiological processes throughout the body, including in the brain. A neural circuit particularly vulnerable to the effects of stress is the hippocampus, a key component of the episodic and spatial memory system in both humans and rodents. Earlier studies have provided snapshots of morphological, molecular, physiological and behavioral changes in the hippocampus following either acute or repeated stress. However, the cumulative impact of repeated stress on in vivo hippocampal physiology remains unexplored. Here we report the stress-induced modulation of the spatially receptive fields of the hippocampal CA1 'place cells' as mice explore familiar and novel tracks after 5 and 10 days of immobilization stress. We find that similar to what has been observed following acute stress, five days of repeated stress results in decreased excitability of CA1 pyramidal cells. Following ten days of chronic stress, however, this decreased hippocampal excitability is no longer evident, suggesting adaptation may have occurred. In addition to these changes in neuronal excitability, we find deficient context discrimination, wherein both short-term and chronic stress impair the ability of the hippocampus to unambiguously distinguish novel and familiar environments. These results suggest that a loss of network flexibility may underlie some of the behavioral deficits accompanying chronic stress.

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. One possible explanation for these inconsistent results is that cytokines may disrupt specific neural processes underlying some forms of memory but not others. In an earlier study, we tested the effect of systemic administration of bacterial lipopolysaccharide (LPS) on retrieval of hippocampus-dependent context memory and neural circuit function in CA3 and CA1 (Czerniawski and Guzowski, 2014). Paralleling impairment in context discrimination memory, we observed changes in neural circuit function consistent with disrupted pattern separation function. In the current study we tested the hypothesis that acute neuroinflammation selectively disrupts memory retrieval in tasks requiring hippocampal pattern separation processes. Male Sprague-Dawley rats given LPS systemically prior to testing exhibited intact performance in tasks that do not require hippocampal pattern separation processes: novel object recognition and spatial memory in the water maze. By contrast, memory retrieval in a task thought to require hippocampal pattern separation, context-object discrimination, was strongly impaired in LPS-treated rats in the absence of any gross effects on exploratory activity or motivation. These data show that LPS administration does not impair memory retrieval in all hippocampus-dependent tasks, and support the hypothesis that acute neuroinflammation impairs context discrimination memory via disruption of pattern separation processes in hippocampus.

Some key parameters in contextual fear conditioning and extinction in adult rats.

Contextual fear conditioning is a behavioral paradigm used to assess hippocampal-dependent memory in experimental animals. Perception of the context depends on activation of a distinct population of neurons in the hippocampus and in hippocampal-related areas that process discrete aspects of context perception. In the absence of any putatively associated cue, the context becomes the salient element that may warn of an upcoming aversive event; and in particular conditions, animals generalize this warning to any new or similar context. In this study we evaluated the effects of the number of sessions, the number of unconditioned stimuli per acquisition session and the distribution of extinction sessions to assess fear acquisition and extinction and determine under which conditions generalization occurred in adult, male rats. We observed that the organization and spacing of sessions were relevant factors in the acquisition and extinction of contextual fear memories. Extinction occurred with significantly greater robustness when sessions were spread over two days. Furthermore, results indicated that exposure to a single 0.3 mA, 0.5 s footshock in two different sessions could produce context-specific fear, while more acquisition sessions or more footshocks within a single session produced a generalization of the fear response to a new context. Notably, when generalization occurred, successive re-exposure to the generalized context produced extinction in a similar way to the paired exposure. Together, the present findings identify clear procedural and behavioral parameters amenable to neural systems analysis of three clinically relevant outcomes of contextual fear conditioning, i.e., memory acquisition, storage and extinction.

Heparan Sulfates Regulate Axonal Excitability and Context Generalization through Ca2+/Calmodulin-Dependent Protein Kinase II.

Our previous studies demonstrated that enzymatic removal of highly sulfated heparan sulfates with heparinase 1 impaired axonal excitability and reduced expression of ankyrin G at the axon initial segments in the CA1 region of the hippocampus ex vivo, impaired context discrimination in vivo, and increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity in vitro. Here, we show that in vivo delivery of heparinase 1 in the CA1 region of the hippocampus elevated autophosphorylation of CaMKII 24 h after injection in mice. Patch clamp recording in CA1 neurons revealed no significant heparinase effects on the amplitude or frequency of miniature excitatory and inhibitory postsynaptic currents, while the threshold for action potential generation was increased and fewer spikes were generated in response to current injection. Delivery of heparinase on the next day after contextual fear conditioning induced context overgeneralization 24 h after injection. Co-administration of heparinase with the CaMKII inhibitor (autocamtide-2-related inhibitory peptide) rescued neuronal excitability and expression of ankyrin G at the axon initial segment. It also restored context discrimination, suggesting the key role of CaMKII in neuronal signaling downstream of heparan sulfate proteoglycans and highlighting a link between impaired CA1 pyramidal cell excitability and context generalization during recall of contextual memories.

An integrative systems biology view of host-pathogen interactions: The regulation of immunity and homeostasis is concomitant, flexible, and smart.

The systemic bio-organization of humans and other mammals is essentially "preprogrammed", and the basic interacting units, the cells, can be crudely mapped into discrete sets of developmental lineages and maturation states. Over several decades, however, and focusing on the immune system, we and others invoked evidence - now overwhelming - suggesting dynamic acquisition of cellular properties and functions, through tuning, re-networking, chromatin remodeling, and adaptive differentiation. The genetically encoded "algorithms" that govern the integration of signals and the computation of new states are not fully understood but are believed to be "smart", designed to enable the cells and the system to discriminate meaningful perturbations from each other and from "noise". Cellular sensory and response properties are shaped in part by recurring temporal patterns, or features, of the signaling environment. We compared this phenomenon to associative brain learning. We proposed that interactive cell learning is subject to selective pressures geared to performance, allowing the response of immune cells to injury or infection to be progressively coordinated with that of other cell types across tissues and organs. This in turn is comparable to supervised brain learning. Guided by feedback from both the tissue itself and the neural system, resident or recruited antigen-specific and innate immune cells can eradicate a pathogen while simultaneously sustaining functional homeostasis. As informative memories of immune responses are imprinted both systemically and within the targeted tissues, it is desirable to enhance tissue preparedness by incorporating attenuated-pathogen vaccines and informed choice of tissue-centered immunomodulators in vaccination schemes. Fortunately, much of the "training" that a living system requires to survive and function in the face of disturbances from outside or within is already incorporated into its design, so it does not need to deep-learn how to face a new challenge each time from scratch. Instead, the system learns from experience how to efficiently select a built-in strategy, or a combination of those, and can then use tuning to refine its organization and responses. Efforts to identify and therapeutically augment such strategies can take advantage of existing integrative modeling approaches. One recently explored strategy is boosting the flux of uninfected cells into and throughout an infected tissue to rinse and replace the infected cells.

Enhancement of select cognitive domains with rosiglitazone implicates dorsal hippocampus circuitry sensitive to PPARγ agonism in an Alzheimer's mouse model.

INTRODUCTION: Several clinical studies have tested the efficacy of insulin-sensitizing drugs for cognitive enhancement in Alzheimer's disease (AD) patients, as type 2 diabetes (T2D) is a well-recognized risk factor for AD. Pilot studies assessing FDA-approved diabetes drugs in subjects with early-stage disease have found cognitive benefit in subjects comorbid for insulin resistance. In AD mouse models with concomitant insulin resistance, we have shown that 4 weeks of RSG can reverse peripheral and central insulin resistance concomitant with rescue of hippocampus-dependent fear learning and memory and hippocampal circuitry deficits in 9-month-old (9MO) Tg2576 mice with no effect in wild-type (WT) mice. Bioinformatics analysis of genomic and proteomic data reveals an intimate link between PPARγ and MAPK/ERK signaling in the hippocampus. We then demonstrated a direct interaction between PPARγ and phospho-ERK in vitro and in vivo during memory consolidation. The translational value of this discovery is evidenced by the positive correlational relationship between human AD postmortem brain levels of pERK-PPARγ nuclear complexes with cognitive reserve. METHODS: We tested whether insulin sensitizer therapy could rescue spatial navigation, context discrimination, and object recognition learning and memory in aged wild-type and Tg2576 mice in addition to hippocampus-dependent contextual fear learning and memory, as we have previously reported. RESULTS: We found that rosiglitazone treatment improved cognitive domains that predominantly rely upon the dorsal hippocampus rather than those that additionally engage the ventral hippocampus. CONCLUSION: These results suggest that insulin sensitizer therapy with rosiglitazone improved age- and AD-related learning and memory deficits in circuit selective ways.

Traumatic brain injury and hippocampal neurogenesis: Functional implications.

In the adult brain, self-renewing radial-glia like (RGL) progenitor cells have been shown to reside in the subventricular zone and the subgranular zone of the hippocampus. A large body of evidence shows that experiences such as learning, enriched environment and stress can alter proliferation and differentiation of RGL progenitor cells. The progenitor cells present in the subgranular zone of the hippocampus divide to give rise to newborn neurons that migrate to the dentate gyrus where they differentiate into adult granule neurons. These newborn neurons have been found to have a unique role in certain types of hippocampus-dependent learning and memory, including goal-directed behaviors that require pattern separation. Experimental traumatic brain injury (TBI) in rodents has been shown to alter hippocampal neurogenesis, including triggering the acute loss of newborn neurons, as well as progenitor cell hyper-proliferation. In this review, we discuss the role of hippocampal neurogenesis in learning and memory. Furthermore, we review evidence for the molecular mechanisms that contribute to newborn neuron loss, as well as increased progenitor cell proliferation after TBI. Finally, we discuss strategies aimed at enhancing neurogenesis after TBI and their possible therapeutic benefits.

Sarm1 loss reduces axonal damage and improves cognitive outcome after repetitive mild closed head injury.

One of the consistent pathologies associated with both clinical and experimental traumatic brain injury is axonal injury, especially following mild traumatic brain injury (or concussive injury). Several lines of experimental evidence have demonstrated a role for NAD+ metabolism in axonal degeneration. One of the enzymes that metabolizes NAD+ in axons is Sarm1 (Sterile Alpha and TIR Motif Containing 1), and its activity is thought to play a key role in axonal degeneration. Using a Sarm1 knock-out mouse, we examined if loss of Sarm1 offers axonal injury protection and improves cognitive outcome after repeated mild closed head injury (rmCHI). Our results indicate that rmCHI caused white matter damage that can be observed in the corpus callosum, cingulum bundle, alveus of the hippocampus, and fimbria of the fornix of wild-type mice. These pathological changes were markedly reduced in injured Sarm1-/- mice. Interestingly, the activation of astrocytes and microglia was also attenuated in the areas with white matter damage, suggesting reduced inflammation. Associated with these improved pathological outcomes, injured Sarm1-/- mice performed significantly better in both motor and cognitive tasks. Taken together, our results suggest that strategies aimed at inhibiting Sarm1 and/or restoring NAD+ levels in injured axons may have therapeutic utility.

Divergent Mechanisms for PPARγ Agonism in Ameliorating Aging-Related Versus Cranial Irradiation-Induced Context Discrimination Deficits.

A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors in a process termed neurogenesis. Adult neurogenesis is limited to specific brain regions in the mammalian brain, such as the subgranular zone (SGZ) of the hippocampus. Alterations in adult neurogenesis appear to be a common hallmark in different neurodegenerative diseases including Alzheimer's disease (AD). We and others have shown that PPARγ agonism improves cognition in preclinical models of AD as well as in several pilot clinical trials. Context discrimination is recognized as a cognitive task supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus that we and others have previously shown declines with age. We therefore postulated that PPARγ agonism would positively impact context discrimination in middle-aged mice via mechanisms that influence proliferation and differentiation of adult-born neurons arising from the SGZ. To achieve our objective, 8-months old mice were left untreated or treated with the FDA-approved PPARγ agonist, rosiglitazone then tested for context discrimination learning and memory, followed by immunofluorescence evaluation of hippocampal SGZ cell proliferation and neuron survival. We found that PPARγ agonism enhanced context discrimination performance in middle-aged mice concomitant with stimulated SGZ cell proliferation, but not new neuron survival. Focal cranial irradiation that destroys neurogenesis severely compromised context discrimination in middle-aged mice yet rosiglitazone treatment significantly improved cognitive performance through an anti-inflammatory mechanism and resurrection of the neurogenic niche. Thus, we have evidence for divergent mechanisms by which PPARγ agonism impinges upon aging-related versus cranial irradiation-induced deficits in context discrimination learning and memory.

Overexpression of activated CaMKII in the CA1 hippocampus impairs context discrimination, but not contextual conditioning.

Calcium/Calmodulin-dependent protein kinase II (CaMKII) plays a key role in the molecular mechanism of memory formation. CaMKII is known to be activated specifically in the activated spines during memory formation. However, it is unclear whether the specific activation of CaMKII is necessary for encoding information. Here, we overexpressed active form of CaMKII (CaMKII*) in the hippocampal CA1 region to activate CaMKII nonspecifically. Moreover, we examined context-discrimination performance of mice. We found that the mice with overexpression of CaMKII* showed impaired context-discrimination ability, while the contextual fear conditioning remained intact. These results indicate that spatial specificity of CaMKII activation is necessary for context discrimination.

Vortioxetine Improves Context Discrimination in Mice Through a Neurogenesis Independent Mechanism.

Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT's effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders.

Impaired contextual fear-conditioning in MAM rodent model of schizophrenia.

The methylazoxymethanol acetate (MAM) rodent neurodevelopmental model of schizophrenia exhibits aberrant dopamine system activation attributed to hippocampal dysfunction. Context discrimination is a component of numerous behavioral and cognitive functions and relies on intact hippocampal processing. The present study explored context processing behaviors, along with dopamine system activation, during fear learning in the MAM model. Male offspring of dams treated with MAM (20mg/kg, i.p.) or saline on gestational day 17 were used for electrophysiological and behavioral experiments. Animals were tested on the immediate shock fear conditioning paradigm, with either different pre-conditioning contexts or varying amounts of context pre-exposure (0-10 sessions). Amphetamine-induced locomotor activity and dopamine neural activity was measured 1-week after fear conditioning. Saline, but not MAM animals, demonstrated enhanced fear responses following a single context pre-exposure in the conditioning context. One week following fear learning, saline rats with 2 or 7min of context pre-exposure prior to fear conditioning also demonstrated enhanced amphetamine-induced locomotor response relative to MAM animals. Dopamine neuron recordings showed fear learning-induced reductions in spontaneous dopamine neural activity in MAM rats that was further reduced by amphetamine. Apomorphine administration confirmed that reductions in dopamine neuron activity in MAM animals resulted from over excitation, or depolarization block. These data show a behavioral insensitivity to contextual stimuli in MAM rats that coincide with a less dynamic dopamine response after fear learning.

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning.

A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38α) signaling pathway, we used the dominant negative mouse model for attenuated p38α activity (DN-p38αAF/+) in which Thr180 and Tyr182 are mutated (T→A/Y→F) to prevent phosphorylation activation (DN-p38αAF/+) and kinase activity. As a result, aged DN-p38αAF/+ mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer's disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual's relative risk. In the present study, we evaluated aged DN-p38αAF/+ and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38αAF/+ and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38αAF/+ exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38αAF/+, we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38αAF/+ mice compared to wildtype littermates. Our findings support the notion that p38α inhibition has therapeutic utility in aging diseases that affect cognition, such as AD.

Neural regions discriminating contextual information as conveyed through the learned preferences of others.

The human brain consists of a network of regions that are engaged when one observes the movements of others. Observing unexpected movements, as defined by the context, often elicits greater activity, particularly in the right posterior superior temporal sulcus (pSTS). This implies that observers use contextual information to form expectations about an agent's goal and subsequent movements. The current study sought to identify regions that support the formation of these context-dependent expectations, with the pSTS being one candidate, given the consistent contextual modulation of its activity. We presented participants with fictitious individuals who had emotion-dependent food preferences, and instructed participants to indicate which food they expected each individual to choose based on the individual's current emotional state. Each individual's preference and emotional state therefore created a context that informed the observer's expectation of the individual's choice. Multi-voxel pattern analysis (MVPA) was used to assess if these different contexts could be discriminated in the pSTS and elsewhere in the brain. No evidence for context discrimination was found in the pSTS. Context discrimination was found instead a network of other brain regions including the anterior medial prefrontal cortex (amPFC), bilateral parietal cortex, left middle temporal gyrus (L MTG) and left anterior temporal lobe (L ATL), which have been previously associated with context processing, and semantic and memory retrieval. All together, these regions possibly support the formation of context-dependent expectations of an agent's goal.