Contexts and catalysts

There has been a historical tension between theories of brain function emphasizing regional specialization and those focusing on integration across regions. This tension continues despite the pervasive use of functional neuroimaging, which enables testing of these theories in the human brain. There are instances of agreement, where regions thought to be critical for a given behavior (e.g., Broca’s area and language production) do become more active when a person engages in that behavior. However, a number of disconcerting results have also been found. These include activation in areas not thought to be important for the behavior, and lack of activation in regions thought to be critical for particular behaviors based on studies of the damaged brain. A recently proposed Neural Context hypothesis of brain function provides a mechanism that can reconcile these apparently disparate findings. The hypothesis states that the functional relevance of a brain area depends on the status of other connected areas—i.e., the context within which the region is operating. A region can participate in several behaviors through variations in its interactions with other areas. It is possible that certain critical nodes serve as Behavioural Catalysts, enabling the transition between behavioral states, without differential alterations in the measured activity. By virtue of its anatomical connections, an area could facilitate a shift in functional connectivity between one set of regions to another. An imaging study on the changing interregional interactions involving the hippocampus in learning and awareness serves as an example of neural context. In this case, the hippocampus may serve to catalyze the transition to awareness.     

A neurodevelopmental model of schizophrenia: neonatal disconnection of the hippocampus

In the context of our current knowledge about schizophrenia, heuristic models of psychiatric disorders may be used to test the plausibility of theories developed on the basis of new emerging biological findings, explore mechanisms of schizophrenia-like phenomena, and develop potential new treatments. In a series of studies, we have shown that neonatal excitotoxic lesions of the rat ventral hippocampus (VH) may serve as a heuristic model. The model appears to mimic a spectrum of neurobiological and behavioral features of schizophrenia, including functional pathology in presumably critical brain regions interconnected with the hippocampal formation and targeted by antipsychotic drugs - the striatum/nucleus accumbens and the prefrontal cortex, and leads in adolescence or early adulthood to the emergence of abnormalities in a number of dopamine related behaviors. Moreover, our data show that even transient inactivation of the ventral hippocampus during a critical period of development, that produces subtle, if any, anatomical changes in the hippocampus, may be sufficient to disrupt normal maturation of the prefrontal cortex (and perhaps, other interconnected late maturing regions) and trigger behavioral changes similar to those observed in animals with the permanent excitotoxic lesion. These results represent a potential new model of aspects of schizophrenia without a gross anatomical lesion.     

The serotonergic and noradrenergic systems of the hippocampus: their interactions and the effects of antidepressant treatments

Previous reviews have well illustrated how antidepressant treatments can differentially alter several neurotransmitter systems in various brain areas. This review focuses on the effects of distinct classes of antidepressant treatments on the serotonergic and the noradrenergic systems of the hippocampus, which is one of the brain limbic areas thought to be relevant in depression: it illustrates the complexity of action of these treatments in a single brain area. First, the basic elements (receptors, second messengers, ion channels, ...) of the serotonergic and noradrenergic systems of the hippocampus are revisited and compared. Second, the extensive interactions occurring between the serotonergic and the noradrenergic systems of the brain are described. Finally, issues concerning the short- and long-term effects of antidepressant treatments on these systems are broadly discussed. Although there are some contradictions, the bulk of data suggests that antidepressant treatments work in the hippocampus by increasing and decreasing, respectively, serotonergic and noradrenergic neurotransmission. This hypothesis is discussed in the context of the purported function of the hippocampus in the formation of memory traces and emotion-related behaviors.     

Neonatal disconnection of the rat hippocampus: a neurodevelopmental model of schizophrenia

In the context of our current knowledge about schizophrenia, heuristic models of psychiatric disorders may be used to test the plausibility of theories developed on the basis of new emerging biological findings, explore mechanisms of schizophrenia-like phenomena, and develop potential new treatments. In a series of studies, we have shown that neonatal excitotoxic lesions of the rat ventral hippocampus (VH) may serve as a heuristic model. The model appears to mimic a spectrum of neurobiological and behavioral features of schizophrenia, including functional pathology in presumably critical brain regions interconnected with the hippocampal formation and targeted by antipsychotic drugs (the striatum/nucleus accumbens and the prefrontal cortex), and leads in adolescence or early adulthood to the emergence of abnormalities in a number of dopamine-related behaviors. Moreover, our data show that even transient inactivation of the VH during a critical period of development, which produces subtle, if any, anatomical changes in the hippocampus, may be sufficient to disrupt normal maturation of the prefrontal cortex (and perhaps, other interconnected latematuring regions) and trigger behavioral changes similar to those observed in animals with the permanent excitotoxic lesion. These results represent a potential new model of aspects of schizophrenia without a gross anatomical lesion.     

The ontogeny of feeding and drinking: Effects of early brain damage

Research concerned with the effects of early brain damage upon the ontogeny of feeding and drinking behaviors is described. The neural areas discussed are the olfactory bulbs, frontal cortex, lateral hypothalamic area, substantia nigra-nigrostriatal bundle, reticular formation, and central gustatory structures. The effects of early (infancy) and late (adulthood) brain damage upon consummatory behaviors are described, and critical ages are defined. For each neural area, the critical age is the age during development when damage to a specified neural area produces consummatory behavior alteration which is equivalent to consummatory behavior alteration produced when the neural area is destroyed in adults. Critical ages were found to differ for different neural areas, e.g., 7–8 days of age for lateral hypothalamic area, 60 days of age for frontal cortex. These critical ages may serve to signal the ontogenetic onset of function of neural substrates of consummatory behaviors and/or neural plasticity preserves function when damage occurs prior to the critical age.     

Immediate early gene activation throughout the brain is associated with dynamic changes in social context

Social competence is dependent on successful processing of social context information. The social opportunity paradigm is a methodology in which dynamic shifts in social context are induced through removal of the alpha male in a dominance hierarchy, leading to rapid ascent in the hierarchy of the beta male and of other subordinate males in the social group. In the current study, we use the social opportunity paradigm to determine what brain regions respond to this dynamic change in social context, allowing an individual to recognize the absence of the alpha male and subsequently perform status-appropriate social behaviors. Replicating our previous work, we show that following removal of the alpha male, beta males rapidly ascend the social hierarchy and attain dominant status by increasing aggression towards more subordinate individuals. Analysis of patterns of Fos immunoreactivity throughout the brain indicates that in individuals undergoing social ascent, there is increased activity in regions of the social behavior network, as well as the infralimbic and prelimbic regions of the prefrontal cortex and areas of the hippocampus. Our findings demonstrate that male mice are able to respond to changes in social context and provide insight into the how the brain processes these complex behavioral changes.     

Dorsal hippocampal regulation of memory reconsolidation processes that facilitate drug context-induced cocaine-seeking behavior in rats

Exposure to a cocaine-paired context increases the propensity for relapse in cocaine users and prompts cocaine-seeking behavior in rats. According to the reconsolidation hypothesis, upon context re-exposure, established cocaine-related associations are retrieved and can become labile. These associations must undergo reconsolidation into long-term memory to effect enduring stimulus control. The dorsal hippocampus (DH), dorsolateral caudate–putamen and dorsomedial prefrontal cortex are critical for the expression of context-induced cocaine seeking, and these brain regions may also play a role in the reconsolidation of cocaine-related memories that promote this behavior. To test this hypothesis, rats were trained to press a lever for unsignaled cocaine infusions (0.2 mg/infusion, i.v.) in a distinct environmental context (cocaine-paired context), followed by extinction training in a different context (extinction context). Rats were then re-exposed to the cocaine-paired context for 15 min in order to reactivate cocaine-related memories or received comparable exposure to a novel unpaired context. Immediately thereafter, rats received bilateral microinfusions of the protein synthesis inhibitor anisomycin, the sodium channel blocker tetrodotoxin or vehicle into one of the above brain regions. After additional extinction training in the extinction context, reinstatement of cocaine-seeking behavior (i.e., non-reinforced lever presses) was assessed in the cocaine-paired context. Tetrodotoxin, but not anisomycin, administered into the DH inhibited drug context-induced cocaine-seeking behavior in a memory reactivation-dependent manner. Other manipulations failed to alter this behavior. These findings suggest that the DH facilitates the reconsolidation of associative memories that maintain context-induced cocaine-seeking behavior, but it is not the site of anisomycin-sensitive memory restabilization per se .     

Intrinsic connectivity between the hippocampus,nucleus accumbens,and ventral tegmental area in humans

Recent studies suggest that memory formation in the hippocampus is modulated by the motivational significance of events, allowing past experience to adaptively guide behavior. The effects of motivation on memory are thought to depend on interactions between the hippocampus, the ventral tegmental area (VTA), and the nucleus accumbens (NAcc). Indeed, animal studies reveal anatomical pathways for circuit‐level interaction between these regions. However, a homologue circuit connectivity in humans remains to be shown. We characterized this circuitry in humans by exploiting spontaneous low‐frequency modulations in the fMRI signal (termed resting‐state functional connectivity), which are thought to reflect functionally related regions and their organization into functional networks in the brain. We examined connectivity in this network across two datasets (hi‐resolution, n = 100; standard resolution, n = 894). Results reveal convergent connectivity between the hippocampus, and both the NAcc and the VTA centered on ventral regions in the body of the hippocampus. Additionally, we found individual differences in the strength of connectivity within this network. Together, these results provide a novel task‐independent characterization of circuitry underlying interactions between the hippocampus, NAcc, and VTA and provide a framework with which to understand how connectivity might reflect and constrain the effects of motivation on memory. © 2012 Wiley Periodicals, Inc.     

Viewing Ambiguous Social Interactions Increases Functional Connectivity between Frontal and Temporal Nodes of the Social Brain

Social behavior is coordinated by a network of brain regions, including those involved in the perception of social stimuli and those involved in complex functions, such as inferring perceptual and mental states and controlling social interactions. The properties and function of many of these regions in isolation are relatively well understood, but less is known about how these regions interact while processing dynamic social interactions. To investigate whether the functional connectivity between brain regions is modulated by social context, we collected fMRI data from male monkeys (Macaca mulatta) viewing videos of social interactions labeled as “affiliative,” “aggressive,” or “ambiguous.” We show activation related to the perception of social interactions along both banks of the superior temporal sulcus, parietal cortex, medial and lateral frontal cortex, and the caudate nucleus. Within this network, we show that fronto-temporal functional connectivity is significantly modulated by social context. Crucially, we link the observation of specific behaviors to changes in functional connectivity within our network. Viewing aggressive behavior was associated with a limited increase in temporo-temporal and a weak increase in cingulate-temporal connectivity. By contrast, viewing interactions where the outcome was uncertain was associated with a pronounced increase in temporo-temporal, and cingulate-temporal functional connectivity. We hypothesize that this widespread network synchronization occurs when cingulate and temporal areas coordinate their activity when more difficult social inferences are being made.SIGNIFICANCE STATEMENT Processing social information from our environment requires the activation of several brain regions, which are concentrated within the frontal and temporal lobes. However, little is known about how these areas interact to facilitate the processing of different social interactions. Here we show that functional connectivity within and between the frontal and temporal lobes is modulated by social context. Specifically, we demonstrate that viewing social interactions where the outcome was unclear is associated with increased synchrony within and between the cingulate cortex and temporal cortices. These findings suggest that the coordination between the cingulate and temporal cortices is enhanced when more difficult social inferences are being made.     

Temporal lobe interictal epileptic discharges affect cerebral activity in "default mode" brain regions

A cerebral network comprising precuneus, medial frontal, and temporoparietal cortices is less active both during goal-directed behavior and states of reduced consciousness than during conscious rest. We tested the hypothesis that the interictal epileptic discharges affect activity in these brain regions in patients with temporal lobe epilepsy who have complex partial seizures. At the group level, using electroencephalography-correlated functional magnetic resonance imaging in 19 consecutive patients with focal epilepsy, we found common decreases of resting state activity in 9 patients with temporal lobe epilepsy (TLE) but not in 10 patients with extra-TLE. We infer that the functional consequences of TLE interictal epileptic discharges are different from those in extra-TLE and affect ongoing brain function. Activity increases were detected in the ipsilateral hippocampus in patients with TLE, and in subthalamic, bilateral superior temporal and medial frontal brain regions in patients with extra-TLE, possibly indicating effects of different interictal epileptic discharge propagation.     

Functional interaction between the dorsal hippocampus and the striatum in visual discrimination learning

The hippocampus and the striatum have traditionally been considered as part of different and independent memory systems. However, there is evidence that supports a functional interaction between the hippocampus and the dorsal striatum at least in particular learning tasks. Here, we evaluated the functional contribution of both brain regions in a visual discrimination learning task using cytochrome c oxidase (CO) quantitative histochemistry. Compared with other brain metabolic mapping techniques, CO activity reflects steady-state neuronal energy demand. Rats were trained for 6 days in a water T-maze to find a hidden escape platform associated with an intramaze visual cue. A control group of animals swam for an equivalent amount of time compared as the trained group but without any escape platform available. After finishing the behavioral task, CO activity was measured in subdivisions of the dorsal hippocampus and the dorsal striatum in both groups. Results show significantly higher CO activity in the CA1 area and the dentate gyrus of the dorsal hippocampus in the trained rats compared with the control group. In addition, a significant negative functional cross-correlation between area CA1 of the dorsal hippocampus and the anterodorsal striatum was found. Our results support current theories on competitive interaction of different memory systems during visual discrimination learning.     

Complimentary roles of the hippocampus and retrosplenial cortex in behavioral context discrimination

Complex cognitive functions, such as learning and memory, arise from the interaction of multiple brain regions that comprise functional circuits and different components of these circuits make unique contributions to learning. The hippocampus and the retrosplenial cortex (RSC) are anatomically interconnected and both regions are involved in learning and memory. Previous studies indicate that the hippocampus exhibits unique firing patterns for different contexts and that RSC neurons selectively respond to cues that predict reinforcement or the need for a behavioral response, suggesting a hippocampal role in encoding contexts and an RSC role in encoding behaviorally significant cues. To test this, we simultaneously recorded hippocampal and RSC neuronal activity as rats learned to discriminate two behavioral contexts. The rats learned to approach the east arm of a plus maze for reward during the first half of each session and to approach the west arm during the second half. The "go east" and "go west" conditions constitute distinct behavioral contexts, which were cued by the reward location. Neurons in both regions developed highly context-specific responses as subjects learned to discriminate the contexts, but the response patterns differed in the two brain regions. Consistent with a context processing role, hippocampal neurons developed context-specific responses to a variety of task stimuli and events. In contrast, RSC neurons only developed context-specific responses to the reward location, which served as the context identifying cue. These results suggest that the hippocampus and RSC play distinct, but complimentary roles in mediating context appropriate memories and behaviors.     

Using animal models to test a neurodevelopmental hypothesis of schizophrenia

A series of studies has shown that neonatal excitotoxic disconnection of the rat ventral hippocampus may serve as a heuristic model of schizophrenia. The model mimics a spectrum of neurobiologic and behavioural features of schizophrenia. It produces functional pathology in critical brain regions implicated in schizophrenia and connected with the hippocampal formation, namely, the striatum, nucleus accumbens and the prefrontal cortex. These brain regions are also targeted by antipsychotic drugs. Neonatal insult leads in young adulthood to the emergence of abnormalities in a number of dopamine-related behaviours. It also models some of the negative aspects of schizophrenia, such as social impairments and working memory deficits. Moreover, our data show that even transient inactivation of the ventral hippocampus during a critical period of development that produces subtle anatomical changes in the hippocampus may be sufficient to trigger behavioural changes similar to those observed in animals with the permanent excitotoxic lesion. The results of bromodeoxyuridine (BrdU) incorporation studies show that this transient disconnection in the CA1 and CA2 area of the hippocampus may have long-lasting consequences for neurogenesis in the dentate gyrus. Our data suggest that neonatal disconnection of the ventral hippocampus alters development and plasticity of prefrontal cortical circuitry and produces a constellation of behavioural and cellular changes that mimic many aspects of schizophrenia. The neonatal hippocampal disconnection model represents a potential new model of schizophrenia without a gross anatomical lesion.     

The medial temporal lobe functional connectivity patterns associated with forming different mental representations

The medial temporal lobes (MTL), and more specifically the hippocampus, are critical for forming mental representations of past experiences—autobiographical memories—and for forming other “nonexperienced” types of mental representations, such as imagined scenarios. How the MTL coordinate with other brain areas to create these different types of representations is not well understood. To address this issue, we performed a task‐based functional connectivity analysis on a previously published dataset in which fMRI data were collected as participants created different types of mental representations under three conditions. One condition required forming and relating together details from a past event (autobiographical task), another required forming and relating together details of a spatial context (spatial task) and another condition required relating together conceptual/perceptual features of an object (conceptual task). We contrasted the connectivity patterns associated with a functionally defined region in the parahippocampal cortex (PHC) and anatomically defined anterior and posterior hippocampal segments across these tasks. Examining PHC connectivity patterns revealed that the PHC seed was distinctly connected to other MTL structures during the autobiographical task, to posterior parietal regions during the spatial task and to a distributed network of regions for the conceptual task. Examining hippocampal connectivity patterns revealed that the anterior hippocampus was preferentially connected to regions of default mode network during the autobiographical task and to areas implicated in semantic processing for the conceptual task whereas the posterior hippocampus was preferentially connected to medial‐posterior regions of the brain during the spatial task. We interpret our findings as evidence that there are MTL‐guided networks for forming distinct types of mental representations that align with functional distinctions within the hippocampus.     

The role of olfactory stimulus in adult mammalian neurogenesis

Neurogenesis occurs in the adult mammalian brain in discrete regions related to olfactory sensory signaling and integration. The olfactory receptor cell population is in constant turn-over through local progenitor cells. Also, newborn neurons are added to the olfactory bulbs through a major migratory route from the subventricular zone, the rostral migratory stream. The olfactory bulbs project to different brain structures, including: piriform cortex, amygdala, entorhinal cortex, striatum and hippocampus. These structures play important roles in odor identification, feeding behavior, social interactions, reproductive behavior, behavioral reinforcement, emotional responses, learning and memory. In all of these regions neurogenesis has been described in normal and in manipulated mammalian brain. These data are reviewed in the context of a sensory-behavioral hypothesis on adult neurogenesis that olfactory input modulates neurogenesis in many different regions of the brain.     

Multivariate pattern analysis of the human medial temporal lobe revealed representationally categorical cortex and representationally agnostic hippocampus

Contemporary theories of the medial temporal lobe (MTL) suggest that there are functional differences between the MTL cortex and the hippocampus. High‐resolution functional magnetic resonance imaging and multivariate pattern analysis were utilized to study whether MTL subregions could classify categories of images, with the hypothesis that the hippocampus would be less representationally categorical than the MTL cortex. Results revealed significant classification accuracy for faces versus objects and faces versus scenes in MTL cortical regions—parahippocampal cortex (PHC) and perirhinal cortex (PRC)—with little evidence for category discrimination in the hippocampus. MTL cortical regions showed significantly greater classification accuracy than the hippocampus. The hippocampus showed significant classification accuracy for images compared to a nonmnemonic baseline task, suggesting that it responded to the images. Classification accuracy in a region of interest encompassing retrosplenial cortex (RSC) and the posterior cingulate cortex (PCC) posterior to RSC, showed a similar pattern of results to PHC, supporting the hypothesis that these regions are functionally related. The results suggest that PHC, PRC, and RSC/PCC are representationally categorical and the hippocampus is more representationally agnostic, which is concordant with the hypothesis of the role of the hippocampus in pattern separation. © 2014 Wiley Periodicals, Inc.     

Differential functional connectivity of prefrontal and medial temporal cortices during episodic memory retrieval

Some theories of brain function emphasize the interactions between brain areas as the major determinant of cognitive and behavioral operations. We explored such interactions in a PET study of episodic memory retrieval having three retrieval conditions, with differing levels of retrieval success. Functional connectivity of voxels located within Brodmann areas 10 and 45/47 in the right prefrontal cortex (RPFC) and the left hippocampus (LGH) with the rest of the brain was estimated using partial least squares. Area 10 and LGH showed an opposite pattern of functional connectivity, with a large expanse of bilateral limbic cortices that was equivalent in all tasks. However, during high retrieval, area 45/47 was included in this pattern. The results suggest that activity in portions of the RPFC reflects either memory retrieval mode or retrieval success, depending on other brain regions to which it is functionally linked. Hum. Brain Mapping 5:323–327, 1997. © 1997 Wiley-Liss, Inc.     

Hippocampal ripples as a mode of communication with cortical and subcortical areas

Hippocampal sharp wave‐ripple complexes are transient events of highly synchronous neuronal activity that typically occur during “offline” brain states. This endogenous surge of activity consists of behaviorally relevant spiking patterns, describing spatial trajectories. They have been shown to play a critical role in memory consolidation during sleep and in navigational planning during wakefulness. Beyond their local impact on the hippocampal formation, ripples also exert direct and indirect effects on target cortical and subcortical areas, which are thought to play a key role in information processing and semantic network reconfiguration. We review research into the function of hippocampal sharp waves‐ripples, with a special focus on information flow between the hippocampus and its cortical and subcortical targets. First, we briefly review seminal work establishing a causal role of ripple‐related activity in cognitive processes. We then review evidence for a functional interplay between hippocampal ripples and specific patterns of cortical and subcortical activity. Finally, we discuss the critical role of the functional coupling between ripples and other sleep rhythms, including the cortical slow oscillation and thalamocortical sleep spindles.     

Neural systems connecting interoceptive awareness and feelings

In many theories of emotions the representations of bodily responses play an important role for subjective feelings. We tested the hypothesis that the perception of bodily states is positively related to the experienced intensity of feelings as well as to the activity of first-order and second-order brain structures involved in the processing of feelings. Using a heartbeat perception task, subjects were separated into groups with either high or poor interoceptive awareness. During emotional picture presentation we measured high-density EEG and used spatiotemporal current density reconstruction to identify regions involved in both interoceptive awareness and emotion processing. We observed a positive relation between interoceptive awareness and the experienced intensity of emotions. Furthermore, the P300 amplitudes to pleasant and unpleasant pictures were enhanced for subjects with high interoceptive awareness. The source reconstruction revealed that interoceptive awareness is related to an enhanced activation in both first-order structures (insula, somatosensory cortices) and second-order structures (anterior cingulate, prefrontal cortices). We conclude that the perception of bodily states is a crucial determinant for the processing and the subjective experience of feelings.     

Early lead exposure and the hippocampus: a review and recent advances

A review of previous evidence suggests an association between early Pb exposure and hippocampal dysfunction. This report summarizes recent experiments conducted in both our laboratory and others' examining the effects of early Pb exposure on hippocampal morphological development, and behaviors characteristic of hippocampal dysfunction. Following postnatal Pb exposure marked reductions are seen in general hippocampal development and in the axonal and dendritic development of hippocampal dentate granule cells. Correlated with these neuroanatomical changes are Pb induced behavioral changes which show numerous similarities to those behavioral changes seen following damage to both the adult and developing hippocampus. These observations thus support the suggestion that the hippocampus may play a critical role in mediating many of the behavioral changes observed following early Pb exposure, as well as indicate that the hippocampus may serve as an excellent model system for further examining the neurobehavioral effects of Pb. However, as other brain areas are also clearly effected by Pb, alternative explanations for these lead induced behavioral changes are also discussed.