BACKGROUND:People with traumatic brain injury (TBI) often experience fatigue, but an understanding of the neural underpinnings of fatigue following TBI is still lacking. This study used resting-state functional magnetic resonance imaging (rs-fMRI) to examine associations between functional connectivity (FC) changes and task-induced changes in subjective fatigue in people with moderate-severe TBI.METHODS:Sixteen people with moderate-severe TBI and 17 matched healthy controls (HC) performed an adaptive N-back task (working memory task) to induce cognitive fatigue. Before and after the task they rated their state fatigue level and underwent rs-fMRI. Seed-to-voxel analyses with seeds in areas involved in cognitive fatigue, namely the striatum and default mode network (DMN) including, medial prefrontal cortex and posterior cingulate cortex, were performed.RESULTS:The adaptive N-back task was effective in inducing fatigue in both groups. Subjective task-induced fatigue was positively associated with FC between striatum and precuneus in people with TBI, while there was a negative association in HC. In contrast, subjective task-induced fatigue was negatively associated with FC between striatum and cerebellum in the TBI group, while there was no association in HC. Similar associations between task-induced subjective fatigue and DMN FC were found across the groups.CONCLUSIONS:Our results suggest that the subjective experience of fatigue was linked to DMN connectivity in both groups and was differently associated with striatal connectivity in people with moderate-severe TBI compared to HC. Defining fatigue-induced neuronal network changes is pertinent to the development of treatments that target abnormal neuronal activity after TBI.

Arc (Activity-regulated cytoskeleton-associated protein) is an effector neuronal immediate-early gene (IEG) and has been closely linked to behaviorally-induced neuronal plasticity. The present studies examined the regionally selective, dissociable patterns of Arc expression induced by Pavlovian trace fear conditioning, delay fear conditioning, and contextual fear conditioning as well as novel context exposure. This research was guided by anatomical studies identifying heterogeneity of connectivity across the transverse (CA1, CA3) and septo-temporal (dorsal vs. ventral) axes of the hippocampus; companion neuropsychological experiments suggest that these subregions likely play functionally dissociable roles in different forms of hippocampal-dependent learning. Hence the primary goal of the present study was to characterize the expression of Arc protein across both the septotemporal and transverse axes of the hippocampus induced by hippocampal dependent trace fear conditioning and compare these expression patterns to those induced by other fear conditioning paradigms. A second goal of these studies was to explore which specific paradigmatic features of the fear conditioning task itself are responsible for the observed patterns of Arc expression. The results of these studies suggest that, within the dorsal hippocampus, Arc expression in CA3 induced by trace fear conditioning may play a unique role in representing the context, while Arc protein expression within ventral CA3 may reflect CS processing. Arc protein expression in dorsal and ventral CA1 are likely not meaningfully involved in trace fear conditioning as there is either a lack of significant enhancement (dorsal CA1) or enhancement is not unique to subjects trained in trace fear conditioning (ventral CA1). The specific regional pattern of Arc protein enhancement induced by trace fear conditioning may reflect the unique temporal parameters of the task which critically engages the hippocampus in processing both contextual representations as well as the explicit CS. This additional hippocampal processing may account for the greater enhancement in Arc protein in dorsal and ventral CA3 for subjects trained in trace fear conditioning compared to novel context exposure, or contextual and delay fear conditioning.

Mounting evidence suggests that long-lasting, protein synthesis-dependent changes in synaptic strength accompany both the initial acquisition and subsequent recall of specific memories. Within brain areas thought to be important for learning and memory, including the hippocampus, learning-related plasticity is likely mediated in part by NMDA receptor activation and experience-dependent changes in gene expression. In the present study, we examined the role of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) expression in the acquisition, recall, and reconsolidation of memory in a trace fear conditioning paradigm. First, we show that the expression of Arc protein in ventral hippocampus (VH) is dramatically enhanced by memory recall 24 h after the acquisition of trace fear conditioning, and that both memory recall and the associated recall-induced enhancement of Arc expression are blocked by pre-training administration of 2-amino-5-phosphonovaleric acid (APV). Next, we show that while infusion of Arc antisense oligodeoxynucleotides (ODNs) into VH prior to testing had little effect on memory recall, it significantly reduced both Arc protein expression and freezing behavior during subsequent testing sessions. Collectively, these results suggest that Arc/Arg3.1 protein plays an important functional role in both the initial acquisition of hippocampal-dependent memory and the reconsolidation of these memories after recall.

While a number of early studies demonstrated that hippocampal damage attenuates the expression of recent, but not remotely trained tasks, an emerging body of evidence has shown that damage to, or inactivation of, the hippocampus often impairs recall across a wide range of training–testing intervals. Collectively, these data suggest that the time course of hippocampal involvement in the storage or recall of previously-acquired memories may differ according to hippocampal subregion and the particular learning task under consideration. The present study examined the contributions of dorsal (DH) and ventral (VH) hippocampus to the expression of previously-acquired trace fear conditioning, a form of Pavlovian conditioning in which the offset of an initially neutral cue or cues and the onset of an aversive stimulus is separated by a temporal (trace) interval. Specifically, either saline or the GABA-A agonist muscimol was infused into DH or VH prior to testing either 1, 7, 28, or 42days after trace fear conditioning. The results revealed a marked dissociation: pre-testing inactivation of DH failed to impair performance at any time-point, while pre-testing inactivation of VH impaired performance at all time-points. Importantly, pre-testing inactivation of VH had no effect on the performance of previously-acquired delay conditioning, suggesting that the deficits observed in trace conditioning cannot be attributed to a deficit in performance of the freezing response. Collectively, these data suggest that VH, but not DH, remains a neuroanatomical locus critical to the recall or expression of trace fear conditioning over an extended period of time.

A common source of variance (i.e., "general intelligence") underlies an individual's performance across diverse tests of cognitive ability, and evidence indicates that the processing efficacy of working memory may serve as one such source of common variance. One component of working memory, selective attention, has been reported to co-vary with general intelligence, and dopamine D1 signaling in prefrontal cortex can modulate attentional abilities. Based on their aggregate performance across five diverse tests of learning, here we characterized the general cognitive ability (GCA) of CD-1 outbred mice. In response to a D1 agonist (SKF82958, 1 mg/kg), we then assessed the relationship between GCA and activation of D1 receptor (D1R)-containing neurons in the prelimbic region of the medial prefrontal cortex, the agranular insular cortex, and the dorsomedial striatum. Increased activation of D1R-containing neurons in the prelimbic cortex (but not the agranular insular cortex or dorsomedial striatum) was observed in animals of high GCA relative to those of low GCA (quantified by c-Fos activation in response to the D1 agonist). However, a Western blot analysis revealed no differences in the density of D1Rs in the prelimbic cortex between animals of high and low GCA. Last, it was observed that working memory training promoted an increase in animals' GCA and enhanced D1R-mediated neuronal activation in the prelimbic cortex. These results suggest that the sensitivity (but not density) of D1Rs in the prelimbic cortex may both regulate GCA and be a target for working memory training.

• A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers.

The dorsal and ventral subregions of the hippocampus likely play dissociable roles in some forms of learning. For example, we have previously demonstrated that temporary inactivation of ventral, but not dorsal, hippocampus dramatically impaired the acquisition of trace fear conditioning, while temporary inactivation of dorsal, but not ventral, hippocampus impaired spatially guided reinforced alternation (Czerniawski et al. (2009) Hippocampus 19:20–32). Importantly, emerging data suggest that lesions, temporary inactivation, and NMDA receptor antagonism within these subregions can produce quite different patterns of behavioral effects when administered into the same region. Specifically, while neither lesions nor temporary inactivation of dorsal hippocampus impair the acquisition of trace fear conditioning, learning in this paradigm is severely impaired by pre‐training administration of the NMDA receptor antagonist dl ‐2‐phosphonovaleric acid (APV) in dorsal hippocampus; the effect of NMDA receptor antagonism within ventral hippocampus on the acquisition and expression of trace conditioning, or on learning in general, has not yet been systematically explored. The present study extends our previous work examining the differential effect of lesions or inactivation of the dorsal and ventral hippocampal subregions by systematically examining the effect of regionally selective pre‐training or pre‐testing administration of APV on the acquisition and expression of trace and contextual fear conditioning. The results of these studies demonstrate that while pre‐training NMDA receptor antagonism within either the dorsal or ventral subregion of the hippocampus impaired the acquisition of both trace and contextual conditioning, pre‐testing NMDA receptor antagonism within ventral, but not dorsal, hippocampus impaired the expression of previously‐acquired trace and contextual fear conditioning. These data suggest that selectively manipulating the integrity of individual subregions may result in compensatory mechanisms that can support learning, and that NMDA‐dependent plasticity within both dorsal and ventral hippocampus is normally required for the acquisition and maintenance of memory in trace and contextual fear conditioning. © 2011 Wiley Periodicals, Inc.

The effects of aging on cognitive capacities were examined by comparing performance of young and old rats on tasks characterized as dependent on different brain systems. This neuropsychological approach was employed to determine the extent to which multiple neural systems are compromised in aging and whether deterioration of one system correlates with that of another. The two tasks used in the present study were an odor-guided recognition memory task, for which different aspects of performance have been shown to be dependent on the integrity of the orbital prefrontal and perirhinal-entorhinal cortex, and the Morris water maze, for which performance depends on the medial prefrontal cortex and hippocampus. Rats were trained on the recognition memory task under minimal memory load and then challenged with longer memory delays and higher levels of inter-item interference. Considerable variation the of

Long-lasting, experience-dependent changes in synaptic strength are widely thought to underlie the formation of memories. Many forms of learning-related plasticity are likely mediated by NMDA receptor activation and plasticity-related gene expression in brain areas thought to be important for learning and memory, including the hippocampus. Here, we examined the putative role of activity-regulated cytoskeletal-associated protein (Arc), an immediate-early gene (IEG) whose expression is tightly linked to the induction and maintenance of some forms of neuronal plasticity, in hippocampus-dependent and hippocampus-independent forms of learning. The extent to which learning-induced Arc expression may depend on NMDA receptor activation was also assessed. First, we observed an increase in Arc gene and protein products in both dorsal hippocampus (DH) and ventral hippocampus (VH) of male Sprague Dawley rats after hippocampus-dependent trace and contextual fear conditioning, but not after hippocampus-independent delay fear conditioning. Specific knockdown of Arc using antisense oligodeoxynucleotides (ODNs) in DH or VH attenuated the learning-related expression of Arc protein, and resulted in a dramatic impairment in trace and contextual, but not delay, fear conditioning. Finally, pretraining infusions of the NMDA receptor antagonist APV into the DH or VH blocked the learning-induced enhancement of Arc in a regionally selective manner, suggesting that NMDA receptor activation and Arc translation are functionally coupled to support hippocampus-dependent memory for fear conditioning. Collectively these results provide the first evidence suggesting that NMDA receptor-dependent expression of the IEG Arc in both DH and VH likely underlies the consolidation of a variety of forms of hippocampus-dependent learning.

This copy is for your personal, non-commercial use only. clicking here. colleagues, clients, or customers by , you can order high-quality copies for your If you wish to distribute this article to others here. following the guidelines can be obtained by Permission to republish or repurpose articles or portions of articles ): December 22, 2011 www.sciencemag.org (this infomation is current as of The following resources related to this article are available online at http://www.sciencemag.org/content/334/6063/1669.full.html version of this article at: including high-resolution figures, can be found in the online Updated information and services, http://www.sciencemag.org/content/suppl/2011/12/21/334.6063.1669.DC1.html can be found at: Supporting Online Material http://www.sciencemag.org/content/334/6063/1669.full.html#ref-list-1 , 15 of which can be accessed free: cites 53 articles This article

The rapid encoding of contextual memory requires the CA3 region of the hippocampus, but the necessary genetic pathways remain unclear. We found that the activity-dependent transcription factor Npas4 regulates a transcriptional program in CA3 that is required for contextual memory formation. Npas4 was specifically expressed in CA3 after contextual learning. Global knockout or selective deletion of Npas4 in CA3 both resulted in impaired contextual memory, and restoration of Npas4 in CA3 was sufficient to reverse the deficit in global knockout mice. By recruiting RNA polymerase II to promoters and enhancers of target genes, Npas4 regulates a learning-specific transcriptional program in CA3 that includes many well-known activity-regulated genes, which suggests that Npas4 is a master regulator of activity-regulated gene programs and is central to memory formation.

7. Possible contributions of long-term potentiation to the encoding and organization of memory Gary Lynch and Ursula Staubli (University of California, Center for the Neurobiology of Learning and Memory, Irvine, CA, U.S.A.) . . . . . . . . . . . . . . . . . . . . . . . .._.__..............._.................................................................................................................... 7.

Converging evidence examining the effects of post-training manipulations of the hippocampus suggests that the hippocampus may play a time-limited role in the maintenance of a variety of forms of memory. In particular, either lesions or inactivation of the dorsal hippocampus results in many cases in a time-limited retrograde impairment in nondiscriminative contextual conditioning paradigms. However, the extent to which hippocampal manipulations result in a time-limited retrograde amnesia for a variety of forms of learning has recently been called into question (reviewed in Sutherland, Sparks, & Lehmann (2010)). The present study examined the effect of inactivation of the dorsal hippocampus either 7, 28, or 42 days following training in an explicitly nonspatial, discriminative contextual conditioning paradigm (Otto and Poon, 2006, Parsons and Otto, 2008). Inactivation of the dorsal hippocampus resulted in a significant deficit in the expression of contextual conditioning at 7 and 28 days, but not 42 days, following training. Importantly, inactivation of the hippocampus did not affect either baseline freezing levels or conditioning to an explicit CS. Together with previous data exploring hippocampal contributions to discriminative unimodal contextual conditioning, these data suggest that the hippocampus may play a particularly prominent role in the temporary maintenance of memory in discriminative contextual paradigms.

of the original article: There is considerable evidence that the hippocampal system contributes both to (1) the temporary maintenance of memories and to (2) the processing of a particular type of memory representation. The findings on amnesia suggest that these two distinguishing features of hippocampal memory processing are orthogonal. Together with anatomical and physiological data, the neuropsychological findings support a model of cortico-hippocampal interactions in which the temporal and representational properties of hippocampal memory processing are mediated separately. We propose that neocortical association areas maintain shortterm memories for specific items and events prior to hippocampal processing as well as providing the final repositories of long-term memory. The parahippocampal region supports intermediate-term storage of individual items, and the hippocampal formation itself mediates an organization of memories according to relevant relationships among items. Hippocampal-cortical interactions produce (i) strong and persistent memories for events, including their constituent elements and the relationships among them, and (ii) a capacity to express memories flexibly across a wide range of circumstances. Hippocampus, delay neurons, and sensory heterogeneity Michael Colombo and Charles G. Gross "Department of Psychology, University of Otago, Dunedin, New Zealand and "Department of Psychology, Princeton University, Princeton, NJ 08544. colombo@otago.ac.nz Abstract: We raise three issues concerning the Eichenbaum, Otto & Cohen (1994) model. (1) We argue against the strict division of labor that Eichenbaum et al. attribute to neocortical and limbic regions. (2) We raise the possibility that the anterior and posterior portions of the hippocampus may be important for different types of information processing. (3) We argue that, rather than reflecting relational processing, different neural responses to "match" and "nonmatch" trials may relate to different required spatial responses. We raise three issues concerning the Eichenbaum, Otto & Cohen (1994) model. (1) We argue against the strict division of labor that Eichenbaum et al. attribute to neocortical and limbic regions. (2) We raise the possibility that the anterior and posterior portions of the hippocampus may be important for different types of information processing. (3) We argue that, rather than reflecting relational processing, different neural responses to "match" and "nonmatch" trials may relate to different required spatial responses. Eichenbaum, Otto, and Cohen (1994a) present an elegant model of the possible contributions made by the hippocampus and adjoining cortex to the memory process. Briefly, they propose that the neocortex and the parahippocampal region support, respectively, short-term memory (STM) and intermediate-term memory (ITM) of single representations. In contrast, the hippocampus is not concerned with the retention of a single item but is critical for the formation and retention of relational representations and for supporting relational flexibility. We wish to raise three issues regarding the Eichenbaum et al. model. The first issue concerns the idea of delay neurons, that is, neurons that respond during the delay period of a visual delayed matching-to-sample (DMS) task when the animal is presumably remembering visual information. Fuster and Jervey (1981; 1982), who first noted this phenomenon, argue that delay activity represents a neural correlate of the to-be-remembered stimulus. Translated into the Eichenbaum et al. terminology, delay activity would represent retention of a single specific item (for example, the visual sample stimulus). Given that the hippocampus is important for the retention of relations between items rather than retention of specific items, Eichenbaum et al. predict that hippocampal neurons should not show delay activity, or if they do, then the characteristics of the delay activity should be different from that of neocortical delay neurons (for example, they might not show sample-elicited sustained firing throughout the delay period). In a recent study, we (Colombo & Gross 1994) noted a substantial proportion of delay neurons when recording from the hippocampus of monkeys performing either an auditory-visual (AV) or visual-visual (W) DMS task. An example of a hippocampal delay neuron is shown in Figure 1. Overall we found that 33.3% of the hippocampal neurons tested on the W DMS task and 41.3% of the hippocampal neurons tested on the AV DMS task exhibited delay activity. In addition, we noted that over one third of the delay neurons tested on the AV DMS task and over one half of the delay neurons tested on the W DMS task exhibited sample-elicited sustained firing over the delay period, that is, activity that according to Eichenbaum et al. is "consistent with the maintenance of an active perceptual representation." We also recorded from neurons in the inferior temporal (IT) cortex of the same monkeys and noted, in support of Eichenbaum et al., a number of differences in the response characteristics of hippocampal and IT cortex delay neurons. Most pertinent to the present discussion was that IT cortex delay activity was generally more selective in that it tended to occur after one of the sample stimuli and not the other, whereas hippocampal delay activity was generally more nonselective in that it tended to occur after both sample stimuli. (The delay neuron in Fig. 1, for example, exhibits nonselective delay activity.) The percentages of selective and nonselective delay neurons in IT cortex and hippocampus are

Emerging evidence suggests that the hippocampus can be anatomically and functionally dissociated along its septotemporal axis into dorsal and ventral subregions. With respect to function, we have recently demonstrated that pre-training excitotoxic lesions of ventral, but not dorsal, hippocampus impair the acquisition of trace fear conditioning, whereas post-training lesions of either dorsal or ventral hippocampus impair the subsequent expression of trace fear conditioning (Yoon and Otto (2007) Neurobiol Learn Mem 87:464-475). In addition to trace fear conditioning, dorsal and ventral hippocampus appear to be differentially involved in a number of spatial memory tasks. The present study examined the effects of temporary inactivation of dorsal or ventral hippocampus on the acquisition and expression of trace fear conditioning and on performance of a spatial delayed reinforced alternation task. The findings demonstrate a double dissociation of dorsal and ventral hippocampal function: inactivation of ventral, but not dorsal, hippocampus attenuated the acquisition and expression of trace fear conditioning, whereas inactivation of dorsal, but not ventral, hippocampus dramatically impaired performance in the delayed reinforced alternation task. These data further support the notion that dorsal and ventral hippocampus contribute differentially to performance in a variety of paradigms.

The current study examined the effects of temporary inactivation of the DH on freezing, rearing, ambulating, grooming, and whisking behavior in an explicitly nonspatial contextual fear conditioning paradigm in which olfactory stimuli served as temporally and spatially diffuse contexts. Prior either to training, testing, or both, male Sprague-Dawley rats received bilateral microinfusions of saline or the GABA(A) agonist muscimol into the DH. Results indicate that temporary inactivation of DH produced both anterograde and retrograde deficits in contextually conditioned freezing, while sparing the acquisition and expression of freezing to a discrete auditory or olfactory CS. These data suggest that there is a decidedly nonspatial component to the role of DH in contextual conditioning, and that olfactory contextual conditioning is a fruitful means of further exploring this function.

The effect of excitotoxic lesions of dorsal vs. ventral hippocampus on the acquisition and expression of auditory trace fear conditioning was examined in two studies. In Experiment 1, animals received excitotoxic lesions of either the dorsal or ventral hippocampus or sham surgeries one week prior to conditioning, and were tested 24 h later. In Experiment 2, animals received excitotoxic lesions of either the dorsal or ventral hippocampus or sham surgeries 24 h after training, and were tested one week after surgery. Both pre- and post-training lesions of ventral hippocampus impaired the acquisition and expression, respectively, of auditory trace fear conditioning. Pre-training lesions of dorsal hippocampus had no effect on the acquisition of trace fear conditioning, while post-training lesions of dorsal hippocampus dramatically impaired expression during subsequent testing. Although in some cases animals with lesions of ventral hippocampus exhibited locomotor hyperactivity, it is unlikely that the pattern of observed deficits can be attributed to this effect. Collectively these data suggest that the dorsal and ventral hippocampus may contribute differentially to the mnemonic processes underlying fear trace conditioning.

Although there is general consensus that the hippocampus is not critically involved in the acquisition of fear conditioned to an explicit conditioned stimulus (CS), the extent to which the hippocampus participates in contextual fear conditioning remains unclear. To further characterize the potential role of the hippocampus in contextual fear conditioning, the present experiments examined the effect of excitotoxic lesions of dorsal hippocampus on the acquisition of a novel contextual fear conditioning paradigm in which a unimodal (olfactory) cue served to disambiguate discrete "contexts" within a single behavioral training chamber. Selective lesions of dorsal hippocampus severely attenuated olfactory contextual conditioning without affecting conditioning to an explicit auditory or olfactory CS. Additional experiments indicate that these contextual conditioning deficits cannot be attributed to a lesion-induced decrement in olfactory perception, a preferential impairment of "weak" forms of conditioning, or hyperactivity. Thus, the hippocampus appears to contribute importantly to the acquisition of fear conditioned to explicitly nonspatial, unimodal, temporally, and spatially diffuse contextual stimuli.

The basolateral amygdaloid complex (BLA) and orbitofrontal cortex (OFC) share extensive reciprocal connections, and interactions between these regions likely contribute to both mnemonic and affective processes. The present study examined the potential differential contributions of the BLA and OFC to performance of an olfactory discrimination task that incorporates auditory conditioned reinforcement and to expression of immediate post-shock freezing behavior. Damage to the BLA had little effect on performance of the conditioned reinforcement task but abolished immediate post-shock freezing behavior. In contrast, damage to OFC resulted in both a mild but significant performance decrement in the conditioned reinforcement task and a significant attenuation of immediate post-shock freezing behavior. These findings suggest that immediate post-shock freezing behavior is likely critically dependent upon interactions between the BLA and OFC. However, although mnemonic processes underlying accurate performance of the conditioned reinforcement task might be supported by OFC in part, such processes are independent of either the BLA or interactions between these two regions.