Contexts and catalysts: a resolution of the localization and integration of function in the brain

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.     

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 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.     

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.     

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.     

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.     

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 .     

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.     

Sleep-dependent directional coupling between human neocortex and hippocampus

Complex interactions between neocortex and hippocampus are the neural basis of memory formation. Two-step theories of memory formation suggest that initial encoding of novel information depends on the induction of rapid plasticity within the hippocampus, and is followed by a second sleep-dependent step of memory consolidation. These theories predict information flow from the neocortex into the hippocampus during waking state and in the reverse direction during sleep. However, experimental evidence that interactions between hippocampus and neocortex have a predominant direction which reverses during sleep rely on cross-correlation analysis of data from animal experiments and yielded inconsistent results. Here, we investigated directional coupling in intracranial EEG data from human subjects using a phase-modeling approach which is well suited to reveal functional interdependencies in oscillatory data. In general, we observed that the anterior hippocampus predominantly drives nearby and remote brain regions. Surprisingly, however, the influence of neocortical regions on the hippocampus significantly increased during sleep as compared to waking state. These results question the standard model of hippocampal-neocortical interactions and suggest that sleep-dependent consolidation is accomplished by an active retrieval of hippocampal information by the neocortex.     

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.     

A common genetic mechanism underlying susceptibility to posttraumatic stress disorder

We hypothesize that susceptibility to post-traumatic stress disorder (PTSD) may be determined in part by aberrant microtubule-associated protein tau expression in neurons of critical brain structures. The following lines of evidence support this hypothesis. First, epidemiologic data suggest the involvement of genetic factors in the susceptibility to PTSD. Second, the common features of both abnormal tau expression and PTSD include amygdalar and hippocampal atrophy, upregulation of norepinephrine biosynthetic capacity in the surviving locus coeruleus neurons and dysfunction of N-methyl-D-aspartate-receptors. Finally, our experiments using rTg4510 mice, a model that over-expresses human mutant tau and develops age-dependent tauopathy, demonstrate that these animals display circling behavior thought to be related to states of anxiety. To detect the potential molecular mechanisms underlying PTSD episodes, laser-assisted/capture microdissection can be used with microarray analysis as an alternative approach to identify changes in gene expression in excitatory and/or inhibitory neurons in critical brain structures (i.e., hippocampus and amygdala) in response to the onset of PTSD.     

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.     

Encoding novel face-name associations: a functional MRI study

The process of forming new associations between previously unrelated items of information, such as a name and a face, likely requires the integration of activity within multiple brain regions. The hippocampus and related structures in the medial temporal lobe are thought to be particularly critical in binding together items of information. We studied eight healthy young subjects with functional magnetic resonance imaging (fMRI) during the encoding of novel face-name associations compared to viewing repeated face-name pairs. A consistent pattern of activation was observed in the hippocampus, pulvinar nucleus of the thalamus, fusiform and dorsolateral prefrontal cortices across individual subjects. The location of the activation within the hippocampus was more anterior than previously reported in studies using similar novel vs. repeated paradigms with stimuli that did not specifically require relational processing among unrelated items. These data suggest that the process of forming new face-name associations is supported by a distributed network of brain regions, and provide additional evidence for the essential role of the hippocampus in associative memory processes.     

Bilateral Rolandic operculum processing underlying heartbeat awareness reflects changes in bodily self‐consciousness

Exteroceptive bodily signals (including tactile, proprioceptive and visual signals) are important information contributing to self‐consciousness. Moreover, prominent theories proposed that visceral signals about internal bodily states are equally or even more important for self‐consciousness. Neuroimaging studies have described several brain regions which process signals related to bodily self‐consciousness (BSC) based on the integration of exteroceptive signals (e.g. premotor cortex, angular gyrus, supramarginal gyrus and extrastriate body area), and that another brain region, the insula/operculum which is involved in interoception and interoceptive awareness, processes signals critical for self‐awareness. Providing evidence for the integration of exteroceptive and interoceptive bodily signals, recent behavioral experiments have demonstrated that the manipulation of interoceptive (e.g. cardiac) signals, coupled with exteroceptive (e.g. visual) signals, also modulates BSC. Does this integration occur within or outside the structures described above? To this end, we adapted a recently designed protocol that uses cardio‐visual stimulation to induce altered states of BSC to fMRI. Additionally, we measured neural activity in a classical interoceptive task. We found six brain regions (bilateral Rolandic operculum, bilateral supramarginal gyrus, right frontal inferior operculum and left temporal superior gyrus) that were activated differently during the interoception task as opposed to a control task. The brain regions which showed the highest selectivity for BSC based on our cardio‐visual manipulation were found in the bilateral Rolandic operculum. Given our findings, we propose that the Rolandic operculum processes integrated exteroceptive–interoceptive signals that are necessary for interoceptive awareness as well as BSC.     

VTA and Anterior Hippocampus Target Dissociable Neocortical Networks for Post-Novelty Enhancements

The detection of novelty indicates changes in the environment and the need to update existing representations. In response to novelty, interactions across the VTA-hippocampal circuit support experience-dependent plasticity in the hippocampus. While theories have broadly suggested plasticity-related changes are also instantiated in the cortex, research has also shown evidence for functional heterogeneity in cortical networks. It therefore remains unclear how the hippocampal-VTA circuit engages cortical networks, and whether novelty targets specific cortical regions or diffuse, large-scale cortical networks. To adjudicate the role of the VTA and hippocampus in cortical network plasticity, we used fMRI to compare resting-state functional coupling before and following exposure to novel scene images in human subjects of both sexes. Functional coupling between right anterior hippocampus and VTA was enhanced following novelty exposure. However, we also found evidence for a double dissociation, with anterior hippocampus and VTA showing distinct patterns of post-novelty functional coupling enhancements, targeting task-relevant regions versus large-scale networks, respectively. Further, significant correlations between these networks and the novelty-related plasticity in the anterior hippocampal-VTA functional network suggest that the central hippocampal-VTA network may facilitate the interactions with the cortex. These findings support an extended model of novelty-induced plasticity, in which novelty elicits plasticity-related changes in both local and global cortical networks.SIGNIFICANCE STATEMENT Novelty detection is critical for adaptive behavior, signaling the need to update existing representations. By engaging the bidirectional hippocampal-VTA circuit, novelty has been shown to induce plasticity-related changes in the hippocampus. However, it remains an open question how novelty targets such plasticity-related changes in cortical networks. We show that anterior hippocampus and VTA target cortical networks at different spatial scales, with respective enhancements in post-novelty functional coupling with a task-relevant cortical region and a large-scale memory network. The results presented here support an extended model of novelty-related plasticity, in which engaging the anterior hippocampal-VTA circuit through novelty exposure propagates cortical plasticity through hippocampal and VTA functional pathways at distinct scales, targeting specific or diffuse cortical networks.     

Development of functional connectivity during adolescence: a longitudinal study using an action-observation paradigm

Successful interpersonal interactions rely on an ability to read the emotional states of others and to modulate one's own behavior in response. The actions of others serve as valuable social stimuli in this respect, offering the observer an insight into the actor's emotional state. Social cognition continues to mature throughout adolescence. Here we assess longitudinally the development of functional connectivity during early adolescence within two neural networks implicated in social cognition: one network of brain regions consistently engaged during action observation and another one associated with mentalizing. Using fMRI, we reveal a greater recruitment of the social-emotional network during the observation of angry hand actions in male relative to female adolescents. These findings are discussed in terms of known sex differences in adolescent social behavior.     

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.     

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.     

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.