Title: Injury characteristics of the Papez circuit in patients with diffuse axonal injury: a diffusion tensor tractography study.

We investigate the characteristics of injury of four portions of the Papez circuit in patients with diffuse axonal injury (DAI), using diffusion tensor tractography (DTT). Thirty-four consecutive patients with DAI and 30 normal control subjects were recruited. Four portions of the Papez circuit were reconstructed: the fornix, cingulum, thalamocingulate tract, and mammillothalamic tract. Analysis of DTT parameters [fractional anisotropy (FA) and tract volume (TV)] and configuration (narrowing, discontinuation, or non-reconstruction) was performed for each portion of the Papez circuit. The Memory Assessment Scale (MAS) was used for the estimation of cognitive function. In the group analysis, decreased fractional anisotropy and tract volume of the entire Papez circuit were observed in the patient group compared with the control group (p < 0.05). In the individual analysis, all four portions of the Papez circuit were injured in terms of DTT parameters or configuration. Positive correlation was observed between TV of the fornix and short-term memory on MAS r = 0.618, p < 0.05), and between FA of the fornix and total memory on MAS (r = 0.613, p < 0.05). We found that all four portions of the Papez circuit in the patient group were vulnerable to DAI, and among four portions of the Papez circuit, the fornix was the most vulnerable portion in terms of injury incidence and severity.

Tuning out the noise: limbic-auditory interactions in tinnitus.

Tinnitus, the most common auditory disorder, affects about 40 million people in the United States alone, and its incidence is rising due to an aging population and increasing noise exposure. Although several approaches for the alleviation of tinnitus exist, there is as of yet no cure. The present article proposes a testable model for tinnitus that is grounded in recent findings from human imaging and focuses on brain areas in cortex, thalamus, and ventral striatum. Limbic and auditory brain areas are thought to interact at the thalamic level. While a tinnitus signal originates from lesion-induced plasticity of the auditory pathways, it can be tuned out by feedback connections from limbic regions, which block the tinnitus signal from reaching auditory cortex. If the limbic regions are compromised, this "noise-cancellation" mechanism breaks down, and chronic tinnitus results. Hopefully, this model will ultimately enable the development of effective treatment.

Neuroética: o cérebro como órgão da ética e da moral / Neuroethics: the brain as the organ of the ethic and the moral

Este artigo discorre sobre o substrato anatômico e neurofisiológico no cérebro desperto que estabelece a normalidade ou o patológico de nossos atos, escolhas, decisões, resolução de dilemas éticos, caráter, emoções e consciência moral, os quais dependem de sistemas e áreas específicas. Para isso, utiliza pesquisas da moderna neuroimagem e testes neuropsicológicos que mapeiam as áreas cerebrais. Dentre essas, os lobos frontais, o sistema límbico, o giro cíngulo, a amígdala temporal e o hipocampo, cuja análise neurofisiológica demonstra que regulam o controle da normalidade psíquica, o autocontrole e, também, o controle da agressividade, violência, livre-arbítrio, responsabilidade e doença mental. Conclui que, se lesadas, essas áreas produzirão respostas anormais ou patológicas nos âmbitos da cognição, julgamento moral e pensamento ético.

Neuroanatomical localization of an internal clock: a functional link between mesolimbic, nigrostriatal, and mesocortical dopaminergic systems.

The effects of selective dopamine (DA) depleting lesions with 6-hydroxydopamine microinjection into the SN, CPu, and NAS, as well as radiofrequency lesions of the CPu on the performance characteristics of rats trained on a single-valued 20-s peak-interval (PI) timing procedure or a double-valued 10-s and 60-s PI procedure were evaluated. A double dissociation in the performance of duration discriminations was found. Rats with CPu lesions were unable to exhibit temporal control of their behavior suggesting complete insensitivity to signal duration but were able to show discrimination of the relative reward value of a signal by differentially modifying their response rates appropriately. In contrast, rats with NAS lesions were able to exhibit temporal control of their behavior by differentially modifying their response rates as a function of signal duration(s), suggesting no impairment of sensitivity to signal duration, but were unable to show discrimination of the relative reward value of a signal.

The role of the rat prelimbic/infralimbic cortex in working memory: not involved in the short-term maintenance but in monitoring and processing functions.

Contrary to human and primate, working memory in the rodent is usually considered as a simple short term memory buffer and mainly investigated using delayed response paradigms. The aim of the present study was to further investigate the role of the rat prelimbic/infralimbic cortex in different spatial delayed tasks in order to dissociate its involvement in temporary storage from other information processes, such as behavioral flexibility and attention. In experiment 1 rats were trained in a standard elimination win-shift task in a radial-arm maze after which a 1-min delay was inserted mid trial. Prelimbic/infralimbic lesions induced only a transient disruption of performance following introduction of the delay. In experiment 2, rats were trained directly in a win-shift task with a 5-min delay that was subsequently extended to 30 min. Prelimbic/infralimbic lesions did not significantly affect behavior. Nevertheless, transient disruptions of performance (correlated with lesion extent) were noted repeatedly in lesioned rats when sets of interfering events were presented. The present findings indicate that prelimbic/infralimbic cortex is not directly involved in the short term maintenance of specific information but is implicated when changes, such as sudden introduction of a delay or exposure to unexpected interfering events, alter the initial situation. It appears that working memory in rodents should be considered, as in humans and primates, to encompass both storage and monitoring functions. The present results along with previous ones strongly suggest that prelimbic/infralimbic cortex is not involved in the temporary on-line storage but rather in the control of information required to prospectively organize the ongoing action.

Differential effects of infralimbic cortical lesions on temperature and locomotor activity responses to feeding in rats.

The time of food availability induces important behavioral and metabolic adaptations. Animals subjected to feeding restricted to a few daytime hours show increased locomotor activity and body temperature in anticipation of mealtime. In addition, animals under ad libitum feeding show a marked postprandial raise in body temperature and in thermogenesis. The areas of the brain commanding these responses to food are partially known. We investigated in the rat the role of the infralimbic area, located in the medial prefrontal cortex, and considered a visceral-autonomic motor area, in the responses to ad libitum or restricted feeding schedule. We performed infralimbic cortex excitotoxic lesions using injections of ibotenic acid, and measured body temperature and locomotor activity by telemetry in rats under ad libitum and restricted feeding conditions. We found that bilateral infralimbic area lesions prevented both the anticipatory and the postprandial increases in core temperature, decreased mean temperature by nearly 0.3 degrees C during both light/dark phases, and increased daily temperature variability. In contrast, the lesion caused a rapid induction of the anticipatory locomotor activity. These results show that behavioral and metabolic responses to the time of food availability are commanded separately and that the infralimbic area is a key structure to adjust the body temperature to an upcoming meal.

A reaffirmation of the retrosplenial contribution to rodent navigation: reviewing the influences of lesion, strain, and task.

Retrosplenial cortex (RS) is situated both anatomically and functionally between neocortical and limbic structures involved in spatial navigation. Initial anatomical, electrophysiological and behavioural evidence in both humans and rodents strongly suggested a role for RS in spatial navigation as well. Later studies using more selective cytotoxic lesions in rodents, however, cast doubt on earlier RS studies by failing to find spatial deficits following RS lesions. Contrasting reports from behavioural results on spatial tasks following RS damage have continued to be reported during the past decade. That RS does indeed contribute spatial behaviour even in rodents has been recently reaffirmed. The ambiguity surrounding RS is shown to result from differences in the choice of spatial tasks and rat strains between studies that find RS deficits and those that do not. The reconciliation of behavioural results following RS lesions strengthens the view that RS forms a part of the neural circuitry that underlies spatial navigation.

Testing the importance of the retrosplenial navigation system: lesion size but not strain matters: a reply to Harker and Whishaw.

In their review on the retrosplenial cortex Harker and Whishaw [Neurosci Biobehav Rev, 2004] claim that there is continued disagreement over the importance of this region for navigation. They argue that discrepancies in the published effects of retrosplenial lesions reflect two principal variables, choice of rat strain and choice of spatial task. In this reply, evidence is provided showing that Harker and Whishaw [Neurosci Biobehav Rev, 2004] have created a misleading impression and, in fact, there is a clear consensus that the rat retrosplenial cortex is necessary for navigation. Likewise, there is no dispute that the effects of retrosplenial lesions will differ for different tests of spatial learning. While Harker and Whishaw [Neurosci Biobehav Rev, 2004] also conclude that choice of rat strain has a critical impact on whether a lesion-induced deficit is found, a comprehensive review of the published data shows no systematic strain difference. There is, however, growing evidence that when interpreting the effects of retrosplenial lesions, account should be given of the lesion method and its interaction with lesion size.

Effects of fimbria-fornix, hippocampus, and amygdala lesions on discrimination between proximal locations.

The conditioned cue preference (CCP) task was used to study the information required to discriminate between spatial locations defined by adjacent arms of an 8-arm radial maze. Normal rats learned the discrimination after 3 unreinforced preexposure (PE) sessions and 4 food paired-unpaired training trials. Fimbria-fornix lesions made before, but not after, PE, and hippocampus lesions made at either time, blocked the discrimination, suggesting that the 2 structures processed different information. Lateral amygdala lesions made before PE facilitated the discrimination. This amygdala-mediated interference with the discrimination was the result of a conditioned approach response that did not discriminate between the 2 arm locations. A hippocampus/fimbria-fornix system and an amygdala system process different information about the same learning situation simultaneously and in parallel.

On the transience of egocentric working memory: evidence from testing the contribution of limbic brain regions.

Rats trained on a nonmatching-to-turn rule revealed that egocentric working memory is readily disrupted, hard to use, and transient. In Experiment 1, rats failed to acquire the rule in a plus-maze. Experiment 2 used 2 different plus-mazes to remove any intramaze cues. Task acquisition occurred only when rats could use direction cues (i.e., nonegocentric cues). In Experiments 3 and 4, a J maze was used to minimize the retention interval and eliminate handling rats within a trial. All rats acquired the nonmatching rule, although a 3-s retention delay severely impaired performance. Fornix lesions transiently disrupted performance of the J-maze task (Experiments 3 and 4), but neither fornix (Experiment 1) nor retrosplenial (Experiment 2) lesions impaired the plus-maze tasks.

Impaired object recognition with increasing levels of feature ambiguity in rats with perirhinal cortex lesions.

It has been proposed that the perirhinal cortex is involved in the representation of the characteristics of objects. In particular it has been proposed that it is critical for discriminating between stimuli which have some features in common and thus it has been described as being involved in resolving feature ambiguity. The present experiments demonstrate that lesions of perirhinal cortex in the rat cause impairments in object recognition which increase with the level of feature ambiguity present in the discrimination. Although increasing feature ambiguity increases the overall difficulty of discriminations, lesions of the perirhinal cortex resulted in a disproportionate impairment when feature ambiguity was increased and not when the difficulty of the discrimination was increased through enlargement of the stimulus set. The present experiments therefore support the view that perirhinal cortex in the rat is critical to resolution of feature ambiguity in stimulus specification.

Selective impairment of reasoning about social exchange in a patient with bilateral limbic system damage.

Social exchange is a pervasive feature of human social life. Models in evolutionary biology predict that for social exchange to evolve in a species, individuals must be able to detect cheaters (nonreciprocators). Previous research suggests that humans have a cognitive mechanism specialized for detecting cheaters. Here we provide neurological evidence indicating that social exchange reasoning can be selectively impaired while reasoning about other domains is left intact. The patient, R.M., had extensive bilateral limbic system damage, affecting orbitofrontal cortex, temporal pole, and amygdala. We compared his performance on two types of reasoning problem that were closely matched in form and equally difficult for control subjects: social contract rules (of the form, "If you take the benefit, then you must satisfy the requirement") and precaution rules (of the form, "If you engage in hazardous activity X, then you must take precaution Y"). R.M. performed significantly worse in social contract reasoning than in precaution reasoning, when compared both with normal controls and with other brain-damaged subjects. This dissociation in reasoning performance provides evidence that reasoning about social exchange is a specialized and separable component of human social intelligence, and is consistent with other research indicating that the brain processes information about the social world differently from other types of information.

Effects of lesions to the glutamatergic afferents to the nucleus accumbens in the modulation of reactivity to spatial and non-spatial novelty in mice.

The purpose of this study was to compare the effects of selective lesions of the three main sources of limbic afferents to the nucleus accumbens-fornix, prelimbic cortex and amygdala-with those induced by N-methyl-D-aspartate receptor blockage in this structure, in a non-associative task designed to estimate the ability of rodents to encode spatial and non-spatial relationships between discrete stimuli. The task consists of placing mice in an open field containing five objects and, after three sessions of habituation, examining their reactivity to object displacement (spatial novelty) and object substitution (object novelty). Focal administrations of the competitive N-methyl-D-aspartate antagonist DL-2-amino-5-phosphonopentanoic acid (0.1 microg/side) induced a selective impairment in the ability of mice to react to the spatial change. Lesions to the different structures affect the response of mice to spatial and non-spatial novelty in different ways. In particular, while fornix lesions induced a decrease in re-exploration of the displaced objects, prelimbic cortex lesions enhanced the exploration of both displaced and non-displaced objects. Finally, the basolateral amygdala lesions did not induce any impairment in the detection of the displaced objects but decreased the latencies to approach novel objects. It is concluded that N-methyl-D-aspartate receptor blockage in the nucleus accumbens subsumes the effects of the three lesions. Some hypotheses on the role of glutamatergic transmission in the accumbens on information processing are briefly discussed.

Striatal dopamine receptors and transporters in monkeys with neonatal temporal limbic damage.

Developmental cortical damage has been implicated in the basic neurobiology of schizophrenia. Adult rhesus monkeys with neonatal temporal limbic damage show a stimulus-dependent disinhibition of subcortical dopamine (DA) release. We measured dopamine D2 receptors and transporters in vivo in rhesus monkeys with neonatal and adult mesial temporal limbic lesions and control monkeys to explore further the effects of this developmental lesion on striatal DA function. All monkeys were studied with [I-123]IBZM SPECT to assess the availability of striatal dopamine D2 receptors and with [I-123]beta-CIT SPECT to measure the availability of dopamine transporters in the striatum. IBZM binding was significantly reduced in monkeys with neonatal limbic lesions. No group difference in beta-CIT binding was found. The reduction in IBZM binding was significantly correlated with subcortical dopamine release after monoaminergic prefrontal stimulation as determined with in vivo microdialysis. Our findings imply specific interactions between age at lesion and the availability of DA transporter and receptors in non-human primates, and suggest that stimulus-dependent DA activity affects the expression of DA receptors.

Limbic-cortical neuronal damage and the pathophysiology of schizophrenia.

Neurobiological studies of patients with schizophrenia suggest that abnormalities of both anatomy and function occur in limbic-cortical structures. An anatomical circuit links the functioning of the ventral striatum (i.e., nucleus accumbens) with the hippocampus and other limbic-cortical structures where neurobiological abnormalities have been found. In animals, lesions of limbic-cortical neurons cause decreases in glutamatergic input to the nucleus accumbens and are also associated with decreases in presynaptic dopamine release, increases in the density of D2-like dopamine receptors, and insensitivity to the actions of dopamine antagonists such as haloperidol. These experiments suggest a plausible pathophysiology of schizophrenia, in that schizophrenic symptoms may be caused by an abnormal dopaminergic state brought about by a primary limbic-cortical lesion and deficits in glutamatergic inputs to the ventral striatum.

Dissociable effects of anterior and posterior cingulate cortex lesions on the acquisition of a conditional visual discrimination: facilitation of early learning vs. impairment of late learning.

Two experiments investigated the effects of quinolinic acid induced lesions of the anterior and posterior cingulate cortices on the acquisition and performance of a conditional visual discrimination (CVD) task, in which rats were required to learn a rule of the type: "If lights are flashing FAST, press the right lever; if SLOW press left". In Experiment 1, animals with lesions of the anterior cingulate cortex (ANT group) demonstrated a significant enhancement in learning during the early stages of task acquisition. Conversely, animals with lesions of the posterior cingulate cortex (POS group) were impaired in learning during the later stages of acquisition. There were no significant differences between the ANT and POS groups on the performance of the task when either variable inter-trial intervals or reduced stimulus durations were imposed. In Experiment 2, the specificity of the lesion effects for processes operative during the early and late stages of learning was tested. Animals were trained to a criterion of 70% correct choices on two consecutive sessions prior to lesioning, and subsequently allowed to continue to acquire the task to the mean asymptotic performance level of 85% correct choices on two consecutive sessions. Animals of the POS group were impaired in learning during this later stage of task acquisition, thus replicating the pattern of results obtained in Experiment 1. The animals in Experiment 2 were then tested following a 30-day retention interval and during extinction (removal of sucrose from the magazine). The extinction test revealed an impairment in the ability of animals in the ANT group to omit lever responses in the absence of reinforcement. These results indicate that the anterior and posterior cingulate cortices are functionally dissociable, and suggest that they may form part of complementary, but competing, learning and memory systems.

Transneuronal changes in dendrites of GABAergic parvalbumin-containing neurons of the rat fascia dentata following entorhinal lesion.

The perforant path fibers from the entorhinal cortex form synapses with both granule cells and GABAergic, parvalbumin-containing (PARV) nongranule cells. The authors recently reported a persistent reduction of PARV-positive dendrites in the termination zones of entorhinal fibers in the hippocampus proper and fascia dentata after lesion of the entorhinal cortex. In the present study the authors analyzed the effects of de-entorhination on the ultrastructure of postsynaptic PARV-positive dendrites in the molecular layer of the fascia dentata. PARV immunocytochemistry was performed 2, 8, 55, and 360 days after an ipsilateral entorhinal lesion and, for comparison, 10 days after an ipsilateral fimbria-fornix transection that disconnects the hippocampus from its septal and commissural afferents. Two days after entorhinal lesion, the authors observed swelling of the tissue close to the hippocampal fissure. Adjacent distal dendritic tips of PARV-positive dentate neurons appeared bloated and reduced in number. Reduction of PARV-positive dendrites in the former perforant path termination zone persisted 55 days after entorhinal lesion and could still observed after postlesional survival times for 1 year. Degenerating axon terminals were still present 55 days following lesion and PARV-positive dendrites exhibited abnormal invaginations. Fimbria transection did not result in similar dendritic changes in PARV-positive neurons. The results indicate a long-lasting process of reorganization in the molecular layer of the fascia dentata following entorhinal lesion and persisting changes in the morphology of PARV-immunoreactive dendrites. Entorhinal fibers seem to play a specific role for the maintenance of these dendrites, since similar changes did not occur following removal of septal and commissural fibers.

Entorhinal cortex lesion induces differential responses in [125I]insulin-like growth factor I, [125I]insulin-like growth factor II and [125I]insulin receptor binding sites in the rat hippocampal formation.

The hippocampus can be induced by deafferentation to selectively reorganize its neuronal input. Entorhinal cortex lesion, which causes degeneration of the perforant pathway, evokes sprouting of septal afferents as well as glutamatergic commissural/associational fibers in the deafferentated zone of the molecular layer of the dentate gyrus. Although the process of reactive synaptogenesis that follows deafferentation has been extensively studied, at present little is known about its molecular basis and the mechanism of initiation. In this study, following unilateral lesion of the entorhinal cortex, the time-course of possible alterations of insulin-like growth factors I and II, and insulin binding sites were evaluated by in vitro quantitative receptor autoradiography. [125I]Insulin-like growth factor I receptor binding sites did not exhibit any significant variation between the contralateral and ipsilateral hippocampal formation at any time periods following lesion except in the molecular layer of the dentate gyrus (P < 0.05) at day 8. However, when compared with the unlesioned animals, a differential time-dependent response of [125I]insulin-like growth factor I binding sites was noted in selective layers of the hippocampus. [125I]Insulin-like growth factor II receptor binding sites showed a significant decrease (P < 0.05) in the ipsilateral granular cell layer of the dentate gyrus only at day 14 post lesion. Interestingly, compared to controls, a dramatic bilateral increase (P < 0.05) in [125I]insulin-like growth factor II binding was evident between days 1 and 8 in most layers of the hippocampal formation. A lesion-induced bilateral increase (P < 0.05) in [125I]insulin binding sites was evident in all layers of the hippocampus between two to eight days and at 30 days post lesion. In selective layers, however, a significant increase (P < 0.05) in [125I]insulin binding sites was also observed at days 1 and 14 after lesion. These results, which are compatible with the process of degeneration and/or sprouting of the terminal fibers, suggest possible involvement of insulin-like growth factors and insulin in the sequence of molecular events that occur to facilitate neuronal repair and to promote neuronal survival following entorhinal cortex lesion.

Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats.

Apolipoprotein E is synthesized and secreted by astrocytes in the hippocampus following lesions of the entorhinal cortex. It was proposed that apolipoprotein E, by analogy to its role in cholesterol transport in circulation, could be involved in the salvage and reutilization of non-esterified cholesterol released during terminal breakdown. The salvaged cholesterol could then be transported to neurons by apolipoprotein E-complexes and taken up via the apolipoprotein E/apolipoprotein B (low-density lipoprotein) receptor. To test this hypothesis, we have examined low-density lipoprotein receptor binding in brain sections of rats undergoing hippocampal reinnervation. The number of neuronal cells labelled by fluorescent Dil-low-density lipoprotein as well as the density of [125I]low-density lipoprotein binding sites in the dentate gyrus were found to increase in parallel with the extent of cholinergic reinnervation occurring in the deafferented hippocampus. In contrast, hippocampal cholesterol synthesis fell by more than 60% at eight days post-lesion, but eventually returned to control levels at 30 days post-lesion. The transient loss of cholesterol synthesis coincided with a peak in hippocampal apolipoprotein E expression. A concomitant accumulation of sudanophilic lipids (cholesterol esters and phospholipids) was detected in the outer molecular layer of the dentate gyrus and in the hilar region. The present findings suggest that non-esterified cholesterol released during terminal breakdown is esterified, transported via the apolipoprotein E transport system to neurons undergoing reinnervation, and take-up through the low-density lipoprotein receptor pathway where it is presumably used as a precursor molecule for the synthesis of new synapses and terminals.