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Anomalous expression of microtubule-associated protein 1B in the hippocampus and cortex of aged rats treated with pentylenetetrazole.

The aim of the present study was to assess the age-dependent response of microtubule-associated protein 1B, a plasticity-associated protein deriving from a late gene, following administration of an epileptogenic stimulus. The effect of a single administration of the convulsant pentylenetetrazole on microtubule-associated protein 1B expression in the hippocampal formation and cortex of three-, 18- and 28-month-old rats was assessed using northern blot analysis, in situ hybridization and immunohistochemistry. In three-month-old rats, we detected initial increases in microtubule-associated protein 1B messenger RNA at 15 h following pentylenetetrazole administration in the granule cells of the dentate gyrus, in the CA3 region of the hippocampus and in layers II/III of the entorhinal cortex, and these reached a maximum at 44 h. However, in the hippocampus and cortex of 18-month-old rats, the peak occurred at 15 h, and in the brains of 28-month-old rats a blunted peak was reached at 3 h. Pentylenetetrazole treatment in young rats resulted in a robust induction of microtubule-associated protein 1B immunoreactivity in the granule cells of the dentate gyrus and in layers II/III of the entorhinal cortex, but also produced a large decrease in the retrosplenial cortex. However, following pentylenetetrazole treatment in older rats, the granule cells of the dentate gyrus were nearly devoid of microtubule-associated protein 1B immunoreactivity, whereas the retrosplenial cortex showed no changes at all, and the entorhinal cortex had an expression pattern similar to that of young rats. Aberrant immunolabeling of microtubule-associated protein 1B occurred in cortical layer VI of the aged rats where, unlike in young rats, there was heavy staining of neuronal somata. These results suggest that the regulation of the plasticity-associated protein microtubule-associated protein 1B is altered in the ageing rat brain, with the peak of expression shifted to earlier times in 18-month-old rats and blunted, variable increases at even earlier times in 28-month-old rats.

Aging↗

Visual attention task performance in Wistar and Lister hooded rats: response inhibition deficits after medial prefrontal cortex lesions.

The prefrontal cortex has traditionally been implicated in a variety of cognitive processes, including memory, attention and decision making. The detection of effects of prefrontal cortex lesions on attention has been shown to depend on the procedure used to assess the attentional process. We therefore investigated the effects of lesions of the prefrontal cortex in two different visual attention tasks, i.e. a three-choice serial reaction time task involving sustained and divided attention processes and a visual timing task involving sustained attention and response inhibition processes. In two rat strains that are frequently used in behavioural analysis, i.e. albino Wistar rats and pigmented Lister Hooded rats, lesions of the medial prefrontal cortex caused a deterioration of performance in both tasks, although the effect lasted much longer in the visual timing task. This latter task proved to be especially sensitive to detect the consequences of medial prefrontal cortex lesions, consisting of a loss of both attention control and response inhibition. In both attention tasks, Wistar rats performed less accurate and made more anticipatory responses than Listers. Strain differences could not entirely be attributed to possible visual deficits in albinos, which was also evident when locomotor activity in an open field and food-motivated behaviour in a hoarding paradigm were assessed. Due to slower habituation rates, Lister rats were more active and displayed little food hoarding behaviour. In Wistar rats, hoarding was disrupted by medial prefrontal cortex lesions, showing the effectiveness of the lesion. The results indicate that, although different rat strains provide different baseline levels of behaviour for testing lesion- or drug-induced behavioural changes, lesions of the medial prefrontal cortex do not only disrupt sustained attention processes, but also induce a strong impairment in response inhibition in both Wistar and Lister rats.

Animals↗

The corticocortical projections of the physiologically defined eye field in the rat medial frontal cortex.

This study investigated in the rat the corticocortical projections of the frontal eye field (FEF), which is located within the medial frontal cortex. The experiments were carried out on Wistar rats. Seven animals received a single iontophoretic injection of Phaseolus vulgaris leucoagglutinin in an FEF site within the medial frontal cortex where intracortical microstimulation elicited eye movements. In these cases, anterogradely labeled fibers and terminal-like elements were found in both hemispheres. The densest labeling was seen in the injected hemisphere, where labeled fibers prevailed in the visual cortex and their laminar distribution differed between the primary and secondary visual cortices. Dense labeled fibers were also seen in the frontal and retrosplenial cortex, whereas a columnar arrangement of terminal-like elements was detected in a restricted part of area 1 of the somatosensory cortex. Contralaterally to the injection site, labeled fibers were distributed mainly in the homotopic region. In two animals, the tracer was injected in a site at the FEF border whose stimulation evoked eye and whisker movements. In these animals, a different distribution of labeling was observed with respect to the other rats in which the tracer was deposited within the FEF, and anterograde labeling was observed in areas 1 and 2 of the parietal cortex of both hemispheres; in addition, no labeling was observed in these cases in the primary visual cortex. These findings suggest that cortical sites confined within the rat FEF are implicated in the control of orienting and exploring behaviors in addition to the control of eye movement.

Animals↗

Ocular dominance in anterior visual cortex in a child demonstrated by the use of fMRI.

Negative signal changes in the visual cortex have been observed during visual stimulation when performing functional magnetic resonance imaging (fMRI) in children. This report investigated whether the ocular dominance, which has been demonstrated in the contralateral anterior visual cortex in adults, could be observed in a child by the use of fMRI. A 5-year-old child was studied using fMRI at 1.5 T during alternating monocular visual stimulation under sedation with morphine and pentobarbital. The functional images were motion corrected, and statistical parametric maps were made by contrasting the left or right eye stimulation conditions vs the right or left eye stimulation conditions, respectively, at each voxel. Areas with negative signal changes were found on the left anterior visual cortex during monocular visual stimulation of the right eye and vice versa. There was no area with negative or positive signal change on the ipsilateral visual cortex to the stimulated eye and no area with positive signal change on the contralateral visual cortex. Contralateral ocular dominance of anterior visual cortex similar to that of adults was demonstrated in this child with a negative correlation with the visual stimulus. This finding suggests that peripheral visual fields are represented in the anterior visual cortex of 5-year-old children.

Child, Preschool↗

Independent parcellation of the embryonic visual cortex and thalamus revealed by combinatorial Eph/ephrin gene expression.

The visual cortex in primates is parcellated into cytoarchitectonically, physiologically, and connectionally distinct areas: the striate cortex (V1) and the extrastriate cortex, consisting of V2 and numerous higher association areas [1]. The innervation of distinct visual cortical areas by the thalamus is especially segregated in primates, such that the lateral geniculate (LG) nucleus specifically innervates striate cortex, whereas pulvinar projections are confined to extrastriate cortex [2--8]. The molecular bases for the parcellation of the visual cortex and thalamus, as well as the establishment of reciprocal connections between distinct compartments within these two structures, are largely unknown. Here, we show that prospective visual cortical areas and corresponding thalamic nuclei in the embryonic rhesus monkey (Macaca mulatta) can be defined by combinatorial expression of genes encoding Eph receptor tyrosine kinases and their ligands, the ephrins, prior to obvious cytoarchitectonic differentiation within the cortical plate and before the establishment of reciprocal connections between the cortical plate and thalamus. These results indicate that molecular patterns of presumptive visual compartments in both the cortex and thalamus can form independently of one another and suggest a role for EphA family members in both compartment formation and axon guidance within the visual thalamocortical system.

Animals↗

Auditory what, where, and when: a sensory somatotopy in lateral premotor cortex.

Recent findings have demonstrated that attention to visual events engages the lateral premotor cortex even in the absence of motor planning. Here, we used functional magnetic resonance imaging to explore acoustically triggered activations within the lateral premotor cortex. Temporal (when), object-related (what), and spatial (where) auditory patterns were to be monitored for violations in a serial prediction task. As a result, we found a modality-dependent modulation for auditory events within the inferior ventrolateral premotor cortex, an area engaged in vocal plans. In addition, however, auditory activations were distributed within the entire premotor cortex depending on which stimulus property was attended to. Attention to where patterns was found to engage fields for gaze and reaching (dorsolateral premotor cortex), what patterns to engage fields for hand movements (superior ventrolateral premotor cortex), and when patterns to engage fields for vocal plans. Together, the findings confirm the idea of a sensory somatotopy in lateral premotor cortex, according to which a perceptual pattern triggers representations within that motor effector which would be most appropriate to generate it as an action effect.

Acoustic Stimulation↗

The role of ipsilateral and contralateral inputs from primary cortex in responses of area 21a neurons in cats.

Neuronal responses in cat visual area 21a were analyzed when the primary visual cortex (areas 17 and 18) was deactivated by cooling. Ipsilateral and contralateral cortices were deactivated separately. Results established that (1) cooling the ipsilateral primary cortex diminished the activity of all area 21a cells and, in 30%, blocked responsiveness altogether, and (2) cooling the contralateral primary cortex initially increased activity in area 21a cells but, with further cooling, reduced it to below the original level although only 9% of cells ceased responding. These findings were then compared to earlier results in which bilateral deactivation of the primary cortex greatly reduced and, in most cases, blocked the activity of area 21a cells (Michalski et al., 1993). Despite the response attenuation following cooling of the primary visual cortex (either ipsilateral or contralateral), neurons of area 21a retained their original orientation specificity and sharpness of tuning (measured as the half-width at half-height of the orientation tuning curve). Direction selectivity also tended to remain unchanged. We concluded that for area 21a cells (1) the ipsilateral primary cortex provides the main excitatory input; (2) the contralateral primary cortex supplies a large inhibitory input; and (3) the nature of orientation specificity, sharpness of orientation tuning, and direction selectivity are largely unaffected by removal of the ipsilateral hemisphere excitatory input or the contralateral hemisphere inhibitory input.

Animals↗

The distribution of corticotectal projection neurons correlates with the interblob compartment in macaque striate cortex.

While much attention has been given to the correlation between cytochrome-oxidase (CO) compartments and patterns of cortico-cortical projections originating from supragranular layers in the striate cortex, little is known in this regard about patterns of cortico-subcortical projections originating from infragranular cortex. We studied the tangential distribution of the striate cortex neurons projecting to the superior colliculus and used two approaches to analyze the relationship of this distribution to the arrangement of CO "blobs." First, chi-square analysis indicated that significantly fewer labeled neurons were found within the CO blob compartment than the number expected for a random distribution. Second, spatial cross-correlation analysis--which circumvents the inherent subjectivity of delineating blob boundaries--revealed an area around blob centers in which there was a decreased probability of encountering labeled cells. The size of this area compared well with that of our outlines of CO blobs. We conclude that corticotectal projection neurons in the striate cortex are distributed preferentially within the interblob compartment of the infragranular striate cortex. These results demonstrate that the spatial distribution of cortico-subcortical projection neurons within infragranular cortex can correlate with the CO architecture of the primary visual cortex.

Animals↗

Cortical projections to anterior inferior temporal cortex in infant macaque monkeys.

Inferior temporal (IT) cortex is a "high-order" region of extrastriate visual cortex important for visual form perception and recognition in adult primates. The pattern of cortical afferents from both ipsilateral and contralateral hemispheres to anterior IT cortex was determined in infant macaque monkeys 7-18 weeks of age following injections of wheat-germ agglutinin-HRP. Within the ipsilateral hemisphere, the locations and laminar distribution of labeled cells were similar to those observed after comparable injections in adult monkeys. Specifically, ipsilateral afferents derived from visual areas V4, TEO, anterior and posterior IT, and STP, from parahippocampal, perirhinal, and parietal zones, and from several anterior zones including lateral and ventral frontal cortex, the insula, and cingulate cortex. Within the contralateral hemisphere, we observed labeled cells in homotopic regions of IT and in parahippocampal and perirhinal areas, as has been reported for adult monkeys. However, we also identified additional contralateral regions not previously known to provide input to anterior IT, including lateral and ventral frontal cortex, cingulate cortex, and STP. Overall, the strongest and most widespread projections from outside the temporal lobe were found in the youngest monkey, suggesting that some of these projections may represent transient circuitry necessary for the development of complex visual response properties in anterior IT.

Afferent Pathways↗

Organization of visual cortex in the mouse revealed by correlating callosal and striate-extrastriate connections.

In this study, we have investigated the organization of mouse visual cortex by correlating in detail the distribution of striate-extrastriate projections with the pattern of callosal connections revealed by the transport of horseradish peroxidase from the contralateral hemisphere. Single injections of 3H-proline into striate cortex produce 8-9 discrete projection fields in the belt of cortex surrounding area 17. The number and arrangement of these fields closely resemble the pattern of extrastriate visual areas in the rat. The callosal pattern is also very similar to that in the rat, and provides a set of landmarks for the location of the striate-recipient zones. Thus, cortical regions containing dense aggregations of callosal cells and terminations surround totally or partially the sparsely callosal striate-recipient zones. By comparing our results with previous accounts of the rat visual plan, we were able to identify in lateral extrastriate cortex of the mouse areas anterolateral (AL), lateromedial (LM), laterointermediate (LI), laterolateral (LL), posterolateral (PL), and posterior (P). We also observed 1-2 projections fields into anteromedial (AM) extrastriate cortex, and one field (S) into the posteromedial border of the head representation in primary somatosensory cortex. Our results support the notions that the visual cortex in the mouse is subdivided into multiple visual areas, and that these areas are arranged according to a plan that is common in rodents.

Animals↗

Receptor occupancy in myocardium, adrenal cortex, and brain by TH-142177, a novel AT1 receptor antagonist in rats, in relation to its plasma concentration and hypotensive effect.

PURPOSE: To study the relationship between angiotensin II (AII) receptor occupancy ex vivo in tissues plasma concentration and hypotensive effect of a novel AII receptor antagonist, TH-142177 and losartan in rats. METHODS: At 2, 8 and 24 hr after oral administration of TH-142177 and losartan in rats, AII receptors in myocardium, adrenal cortex and cerebral cortex were determined by radioligand binding assay using [125I]Sar1,Ile8-AII. Plasma concentrations of both drugs and metabolite in rats were also measured using validated HPLC assays. Further, systolic blood pressure (SBP) in conscious renal hypertensive rats treated orally with TH-142177 and losartan were measured by using a tail cuff plethysmographic method. RESULTS: Oral administration of TH-142177 (1.8 and 5.5 micromol/kg) and losartan (6.5 and 21.7 micromol/kg) in rats brought about dose-dependent decreases in [125I]Sar1,Ile8-AII binding sites (Bmax) in myocardium and adrenal cortex. The extent of receptor occupancy by both drugs in adrenal cortex was maximal at 2 hr later but that in myocardium at 8 hr later. Further, the receptor occupancy was more sustained in myocardium than adrenal cortex. The ex vivo binding affinity of TH-142177 for AII receptors in these tissues was roughly three times higher than that of losartan. Also, cerebral cortical [125I]Sar1,Ile8-AII binding was significantly reduced by oral administration of losartan but not by TH-142177. The time course of AII receptor occupancy by both drugs in adrenal cortex appeared to be in parallel with that of their plasma concentrations, while the time course in myocardium correlated with that of their hypotensive effects rather than plasma concentrations. CONCLUSIONS: TH-142177 produced a relatively selective and sustained occupancy ex vivo of AII receptors in myocardium and adrenal cortex of rats with approximately three times greater potency than losartan. Its time course of myocardial receptor occupancy was in parallel with that of hypotensive effect rather than plasma concentration.

Adrenal Cortex↗

NMDA-dependent and NMDA-independent neural processes in the bicucculline-disinhibited motor cortex of the cat during the acquisition and reproduction of a conditioned paw-on-support placing reflex.

Neuron activity was recorded in the motor area of the cat cortex during acquisition of an operant conditioned reflex consisting of placing the forepaw on a support in conditions of local disinhibition by spontaneous diffusion of the GABA(A) receptor blocker bicucculline from the recording micropipette. The conditioned signal was electrical stimulation of the parietal cortex with a train of 3-5 impulses. Addition of 2-amino-5-phosphopentanoic acid (APV), an NMDA glutamate receptor blocker, led to disappearance of the secondary excitatory components (in the poststimulus interval 30-120 msec) from neuronal responses in the disinhibited cortex both to the "indifferent" (before training) and the conditioned stimulation of the parietal cortex, while excitatory reactions associated with elevation and placing of the paw on the support showed no significant change in the presence of APV. Acquisition of the operant conditioned reflex was accompanied by an increase in the amplitude (p < 0.006) and duration (p < 0.00002) of secondary responses and decreases in their latent periods (p < 0.00002). In some cases--in fixed conditioned reflexes--secondary responses to conditioned stimulation in the disinhibited cortex were transformed into trains of epileptiform discharges. The hypothesis that changes in neuronal reactions in the disinhibited cortex during learning are based on increases in the efficiency of horizontal (collateral) connections between pyramidal neurons in layers II and III of the cortex is discussed.

Animals↗

Top-down signal from prefrontal cortex in executive control of memory retrieval.

Knowledge or experience is voluntarily recalled from memory by reactivation of the neural representations in the cerebral association cortex. In inferior temporal cortex, which serves as the storehouse of visual long-term memory, activation of mnemonic engrams through electric stimulation results in imagery recall in humans, and neurons can be dynamically activated by the necessity for memory recall in monkeys. Neuropsychological studies and previous split-brain experiments predicted that prefrontal cortex exerts executive control upon inferior temporal cortex in memory retrieval; however, no neuronal correlate of this process has ever been detected. Here we show evidence of the top-down signal from prefrontal cortex. In the absence of bottom-up visual inputs, single inferior temporal neurons were activated by the top-down signal, which conveyed information on semantic categorization imposed by visual stimulus-stimulus association. Behavioural performance was severely impaired with loss of the top-down signal. Control experiments confirmed that the signal was transmitted not through a subcortical but through a fronto-temporal cortical pathway. Thus, feedback projections from prefrontal cortex to the posterior association cortex appear to serve the executive control of voluntary recall.

Animals↗

Heterogeneous oxygen extraction in the visual cortex during activation in mild hypoxic hypoxia revealed by quantitative functional magnetic resonance imaging.

Functional magnetic resonance imaging (fMRI) techniques were used to study haemodynamic and metabolic responses in human visual cortex during varying arterial blood oxygen saturation levels (Y(sat), determined by pulse-oximeter) and stimulation with contrast-reversing checkerboards. The visual-evoked potential amplitude remained constant at lowered Y(sat) of 0.82+/-0.03. Similarly, fMRI cerebral blood flow (CBF) responses were unchanged during reduced Y(sat). In contrast, visual cortex volume displaying blood oxygen level-dependent (BOLD) fMRI response decreased as a function of Y(sat), but the BOLD signal change of 3.6%+/-1.4% was constant. Oxygen extraction ratio (OER) during visual activation showed values of 0.26+/-0.03 for normal Y(sat). At lowered Y(sat), two OER patterns were observed. Firstly, a reduced OER of 0.14+/-0.03 in the visual cortex structures showing BOLD in hypoxia was observed. Secondly, signs of much higher OER in other parts of visual cortex were obtained. T2*-weighted magnetic resonance imaging revealed signal increases by 0.8%+/-0.4% with visual activation during lowered Y(sat) in the visual cortex structures, which showed BOLD of 3.6% in magnitude under normoxia. Because the CBF response in the visual cortex was quantitatively similar during stimulation in normoxia and hypoxia, attenuated T2*-weighted signal increase in parts of visual cortex indicated high OER during visual activation in hypoxia, which was close to that encountered in the resting brain. These spatially localised regions of tissue oxygen extraction and metabolism argue for dissociation between CBF and BOLD fMRI signals in mild hypoxia. The findings point to heterogeneity with regard to oxygen requirement and its coupling to the haemodynamic response in the brain.

Adult↗

Ribonucleic acid synthesis in the renal cortex at the initiation of compensatory growth.

The mechanisms responsible for the increase in RNA per cell during the first 48h of renal compensatory growth were studied in the renal cortex. Unilaterally nephrectomized, sham-operated or non-operated rats were used. Incorporation into RNA of labelled precursors was studied in vivo and in vitro. Sham-operation produced significant changes in precursor incorporation, absolute amounts of UTP and RNA, and the rate of RNA synthesis. At 6h after surgery, the amount of RNA decreased in sham-operated controls, whereas that in growing cortex remained unchanged. Incorporation into RNA in vivo was greater in the growing cortex, although the rate of RNA synthesis was not increased. At 24h, precursor incorporation into RNA and UTP and RNA synthesis were all increased in the growing cortex. In contrast with results obtained in vivo, slices of growing cortex incorporated less labelled precursor into RNA than did cortex slices from sham-operated controls, from 3 to 48h. Maximal differences were found from 6 to 24h. An attempt was made to equalize endogenous precursor pool sizes by increasing the concentration of unlabelled uridine in the media; incorporation differences were narrowed significantly. Serum from nephrectomized animals did not increase precursor incorporation into RNA in vitro. An increase in RNA synthesis is an important factor in RNA accretion in the renal cortex beyond 12h of compensatory growth. This is accompanied by increased UTP content and preceded by expansion of other pools. The amount of labelled precursor incorporated into RNA is greatly influenced by its delivery rate to the growing kidney in vivo and by intracellular dilution of expanded precursor pools in vitro.

Animals↗

Changes in limbic dopamine metabolism following quinolinic acid lesions of the left entorhinal cortex in rats.

To examine the effects of lesions of the entorhinal cortex on limbic dopamine (DA) metabolism, DA and its metabolites were assayed in five brain regions (the medial prefrontal cortex, anterior cingulate cortex, caudate-putamen, accumbens nucleus, and lateral amygdala), 14 and 28 days after quinolinic acid or sham lesions of the left entorhinal cortex in rats. Concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) on day 14 in the medial prefrontal cortex, accumbens nucleus, and lateral amygdala of the entorhinal cortex lesioned animals were significantly decreased compared with the controls, but they returned to control levels on day 28. The concentration of DA in the lateral amygdala and spontaneous locomotion to a novel environment were significantly increased on day 28 after the lesion. These results suggest that entorhinal cortex lesions alter mesolimbic dopamine metabolism, particularly in the amygdala.

Amygdala↗

Dorsolateral prefrontal cortex: comparative cytoarchitectonic analysis in the human and the macaque brain and corticocortical connection patterns.

The cytoarchitecture of the human and the macaque monkey dorsolateral prefrontal cortex has been examined in a strictly comparative manner in order to resolve major discrepancies between the available segmentations of this cortical region in the human and the monkey brain. In addition, the connections of the dorsolateral prefrontal cortical areas were re-examined in the monkey. The present analysis showed that only a restricted portion of what had previously been labelled as area 46 in the monkey has the same characteristics as area 46 of the human brain; the remaining part of this monkey region has the characteristics of a portion of the middle frontal gyrus in the human brain that had previously been included as part of area 9. We have labelled this cortical area as 9/46 in both species. These two areas (i.e. 46 and 9/46), which constitute the lower half of the mid-dorsolateral frontal cortex, have a well-developed granular layer IV, and can easily be distinguished from area 9, on the upper part of the mid-dorsolateral region, which does not have a well-developed granular layer IV. Area 9 has the same basic pattern of connections as areas 46 and 9/46, but, unlike the latter areas, it does not receive input from the lateral parietal cortex. Caudal to area 9, on the dorsomedial portion of the frontal cortex, there is a distinct strip of cortex (area 8B) which, unlike area 9, receives significant input from the prestriate cortex and the medial parietal cortex. The present results provide a basis for a closer integration of findings from functional neuroimaging studies in human subjects with experimental work in the monkey.

Animals↗

In vivo assessment of dopamine uptake in rat medial prefrontal cortex: comparison with dorsal striatum and nucleus accumbens.

In vivo electrochemistry was used to characterize dopamine clearance in the medial prefrontal cortex and to compare it with clearance in the dorsal striatum and nucleus accumbens. When calibrated amounts of dopamine were pressure-ejected into the cortex from micropipettes adjacent to the recording electrodes, transient and reproducible dopamine signals were detected. The local application of the selective uptake inhibitors GBR-12909, desipramine, and fluoxetine before the application of dopamine indicated that at the lower recording depths examined (2.5-5.0 mm below the brain surface), locally applied dopamine was cleared from the extracellular space primarily by the dopamine transporter. The norepinephrine transporter played a greater role at the more superficial recording sites (0.5-2.25 mm below the brain surface). To compare clearance of dopamine in the medial prefrontal cortex (deeper sites only), striatum, and nucleus accumbens, varying amounts of dopamine were locally applied in all three regions of individual animals. The signals recorded from the cortex were of greater amplitude and longer time course than those recorded from the striatum or accumbens (per picomole of dopamine applied), indicating less efficient dopamine uptake in the medial prefrontal cortex. The fewer number of transporters in the medial prefrontal cortex may be responsible, in part, for this difference, although other factors may also be involved. These results are consistent with the hypothesis that regulation of dopaminergic function is unique in the medial prefrontal cortex.

Animals↗