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Functional development of the dorsolateral prefrontal cortex: an analysis utlizing reversible cryogenic depression.

The dorsolateral prefrontal cortex of rhesus monkeys was functionally inactivated by local hypothermia as the monkeys performed spatial delayed-response and spatial delayed-alternation tasks at different stages of postnatal development. Cryogenic depression of prefrontal cortex at a temperature sufficient to induce 21--25% decrements in delayed-response performance in 34--36-month-old-monkeys, produced deficits of only 7--8% in 19--31-month-old and no detectable loss in younger monkeys, 9--16 months of age. Delayed-alternation performance was impaired by local hypothermia as early as 8.5 months of age, but maximal cooling-induced deficits on this task were not observed before 33 months of age. Thermal gradients mapped in representative monkeys at different stages of development were remarkable similar, indicating that the age-dependent differences in behavior were not attributable to technical factors. The results obtained in the present study on normal developing monkeys confirm the interpretation of previous research on brain-damaged infants that functional maturation of the dorsolateral prefrontal cortex is protracted over several years of postnatal life, and extends the earlier studies by indicating that the lower limit for maturity of dorsolateral function is close to puberty in this species. Further, the present study revealed that delayed-response and delayed-alternation performance are dissociable dorsolateral functions which achieve maturity at different rates. The convergence of evidence from reversible neural depression and permanent lesion methods provides strong validation for neurobehavioral analysis as a general approach to the study of regional maturation of the brain.

Age Factors

Information about movements in monkeys (Macaca mulatta) with lesions of dorsal prefrontal cortex.

It is not known on what information prefrontal cortex acts. Since it has been suggested that it might operate on information about movements, rhesus monkeys were trained on a counting task testing memory for movements. They had to tap a key until a light went out and then repeat, either immediately or after a delay, the number of presses they had made. Monkeys with lesions of dorsal prefrontal cortex were impaired on this task, unlike monkeys with lesions of sulcus principalis alone. Cortex on the dorsal prefrontal convexity appears to act on information about movements.

Animals

Facilitation of self-stimulation of the prefrontal cortex in rats following chronic administration of spiroperidol or amphetamine.

The effect of chronic administration of spiroperidol, a dopaminergic antagonist, on self-stimulation of the prefrontal cortex was investigated. When spiroperidol was administered either before or after daily self-stimulation tests for 9 days, self-stimulation rates were significantly elevated for several weeks following withdrawal of the drug. Self-stimulation of the nucleus accumbens, supracallosal bundle, and other forebrain sites was not altered, suggesting that the increased self-stimulation of the prefrontal cortex was not due to increased motor activity. Self-stimulation of the prefrontal cortex was also facilitated by chronic administration of d-amphetamine whereas self-stimulation of the supracallosal bundle was suppressed and self stimulation of the nucleus accumbens was unchanged. The results suggest that dopamine modulates self-stimulation of the prefrontal cortex. Additionally, the effects of chronic spiroperidol on self-stimulation of this structure may model the therapeutic effects of neuroleptics in humans.

Amphetamine

Preliminary evidence for a direct projection of the prefrontal cortex to the hippocampus in the squirrel monkey.

Unilateral partial ablations in the medial prefrontal cortex of six squirrel monkeys led to fiber degeneration which followed cingulate and uncinate routes to the hippocampal region. Degenerating fibers were observed primarily in the alvear, but also in the perforant, bundle. Preterminal and terminal debris was seen on basket cells of the stratum oriens and pyramidal cells within the sratum pyramidalis of CA1-3. Since the prefrontal cortex has been shown to receive convergent sensory inputs from both external and internal milieu, this projection may represent the anatomical substrate for the essential influence of this information on the hippocampus proper, and also explain data which show the prefrontal cortex and hippocampus to be integrally related to mechanisms of learning and memory behavior.

Animals

Cortical afferents to the prefrontal cortex of the cat: a study with the horseradish peroxidase technique.

Following horseradish peroxidase (HRP) injections into different areas within the prefrontal cortex (PFC) of the cat, labeled neurons were found in the cingulate and insular cortex. These results demonstrate that the cat's prefrontal cortex is reached directly from these cortical regions, and that the observed cortical projections are similar to those detected in the monkey's prefrontal cortex.

Animals

Subcortical afferents to the prefrontal cortex in rabbits.

The origins of cells projecting to the prefrontal cortex of the rabbit were studied, using horseradish peroxidase (HRP) technique. HRP injected into the prefrontal cortex labeled cells in the basal forebrain, lateral hypothalamus, raphe nuclei and locus coeruleus area on both sides. Labeled cells appeared also in the nucleus medialis dorsalis of the thalamus and other thalamic nuclei on the injection side.

Afferent Pathways

Unit activity of the prefrontal cortex during delayed alternation performance in monkey.

Unit activity in the dorsolateral regions of the prefrontal cortex (s. principalis) of the monkey was analysed by multineuronal recording technique. The sequence during delayed-response alternation included anticipatory stimulus, non-specific expectancy, conditioned cue, delay, trigger stimulus and alternation performance. Food reward completed the sequence. Unit activity in s. principalis was found to be involved in such learning processes as integration of behavioural acts into an accomplished programme and storage of traces in short-term memory. The latter can be observed in successive involvement of neuronal populations during a 10 sec delay as well as in rearrangements of unit activity, the maximum of which shifts to the latest part of the delay period. Unit activity in s. principalis reflects the level of correct response, corresponding correlates of which depend on the level of attention. The dorsolateral prefrontal cortex has structural and functional characteristics for short-term storage of external signals in its neuronal nets according to the level of attention.

Animals

Self-stimulation of the MFB or VTA after microinjection of haloperidol into the prefrontal cortex of the rat.

Haloperidol, a dopamine receptor antagonist, was microinjected in doses of 12 or 24 microng into the prefrontal cortex of the rat. Its effects on self-stimulation of the ventral tegmental area (VTA) or the medial forebrain bundle (MFB) were examined. It was found that these injections failed to attenuate self-stimulation at either structure. However, when haloperidol was injected into the caudate-putamen complex, a decrease in self-stimulation occurred within these structures. These results suggest that dopamine in the medial prefrontal cortex is not necessarily a part of the neurochemical substrate underlying self-stimulation of the ventral tegmental area or medial forebrain bundle.

Animals

The monkey's prefrontal cortex functions in motor programming.

A new experimental approach is presented which resulted in clarification of the specific functions of the monkey’s prefrontal cortex. Monkeys with chronically implanted transcortical nonpolarizable electrodes were trained on delayed response (DR) and visual delayed matching-to-sample (DMS) tasks. The onset of the trial for each group depended upon on-line computer detection of one of the specified events: FN – surface-negative steady potential shifts (SPS) from principalis cortex; MN – a similar SPS from precentral cortex; FB – near baseline SP from principalis cortex; LEM – rightward eye deviations; and YC – controls, with intertrial intervals yoked to those of other monkeys. Monkeys were trained with 1-s cue presentations. on successive delays of 2 to 12 s. The DR acquisition rate by the FN group was substantially faster than that of any other group, as indicated by its mean error that was only 17.24 percent the YC group’s error. The MN and LEM monkeys acquired the task at the same rates as the YCs, while the FB monkeys were the slowest learners. The correct DR performance transferred to testing with constant intertrial intervals (without preconditions). Subsequent on-line tests with brief (0.1 s) cue duration showed high DR performance by the FN, but not by other groups. No similar rapid learning was found with the DMS task. The findings from this, and other experiments, suggest that the major function of principalis cortex is the selection, or programming of delayed spatial choice responses. The view seems consonant with interpretations for the role of the human prefrontal cortex.

Animals

A stereotaxic atlas of the prefrontal cortex of the cat.

A survey of existing atlases of the cat's brain has revealed a lack of coronal sections on the levels of the prefrontal cortex. On the other hand, neurophysiological and behavioral studies of this region have increased greatly in recent years. As the extent of coronal sections through the prefrontal cortex was seen to differ markedly even at separations of 1 mm, a stereotaxic atlas was made on the basis of brain sections of 16 mongrel cats. Brains were cut with the use of the paraffin or freezing method, and stained with cresyl violet, Luxol fast blue, or Kluver-Barrera's combination. Statistical methods were used to yield representative coronal outlines of sections from +20 to +30 mm anterior in 1 mm steps. A comparison with Reinoso-Suarez five coronal sections within this range showed a marked congruence between the two atlases.

Animals

The prefrontal cortex of the cat: anatomical subdivisions based on retrograde labeling of cells in the mediodorsal thalamic nucleus.

Different areas of the frontal cortex of the cat were injected with small amounts of horseradish peroxidase. The region of labeled cells in the mediodorsal nucleus of the thalamus (MD) were related to the injected areas. Distinct relations between subdivisions of MD and of the prefrontal cortex were established: a rather large central sector of MD projects to the gyrus proreus and the anterior parts of the gyri sigmoideus, rectus, and frontalis. A narrow lateral band of anterior MD neurons projects predominantly to an area on both sides of the sulcus praesylvius, whereas a postero-lateral band sends fibers to a region on the ventral anterior sylvian gyrus. The area between the presylvian sulcus and the sylvian gyrus is apparently free of MD afferents, but not of other thalamic afferents. A fourth sector of MD, situated dorsomedially, projects to the middle parts of the gyri rectus and frontalis. And a fifth sector, located ventrally to the dorsomedial MD sector, projects to the ventral part of the gyrus rectus. The established subfields of MD and of the prefrontal cortex are discussed with respect to previous anatomical research in the cat.

Afferent Pathways

Dorsolateral prefrontal cortex lesions and discrimination of movement-produced cues by rhesus monkeys.

Rhesus monkeys were trained on a conditional discrimination in which sequences of either 32 or 64 lever presses served as discriminative stimuli. For half the subjects, reinforcement was contingent upon choice of a red response key following a sequence of 32 presses (FR 32), and a white key after FR 64, with the position of the two key colors randomized across trials. The remaining subjects were reinforced for left key presses after FR 64, and right key presses after FR 32, with key color again randomized across trials. Ablation of dorsolateral prefrontal cortex resulted in postoperative deficits in all subjects, although 6 of 8 eventually remastered the task. This recovery was investigated in a second experiment, in which psychophysical functions were generated by varying the length of the shorter FR. Although dorsolateral lesions again produced a severe disruption in performance, the post-operative functions eventually obtained were identical to the preoperative functions. This pattern of marked impairment in retention of fixed ratio discriminations, but no change in asymptotic capacity, suggests participation of dorsolateral prefrontal cortex in processing kinesthetic information, possibly analogous to the role of inferior temporal cortex in processing visual information.

Animals

Delayed-matching and delayed-response deficit from cooling dorsolateral prefrontal cortex in monkeys.

The hypothesis that the functional integrity of the dorsolateral prefrontal cortex is important for short-term memory of both spatial and nonspatial information was examined. Monkeys were tested in delayed matching-to-sample (DMS) and delayed-response (DR) tasks with delays of 0-32 sec. Testing was carried out under three different conditions: frontal cooling (FC), parietal cooling (PC), and normal temperature (noncooling, NC). Errors, reaction time, and motor activity were recorded. The proportion of correct responses decreased in NC as a function of the delay. This decrease was significantly accentuated by FC, whereas it was not modified by PC. At each delay, the decrement elicited by FC was as large in DR as in DMS. Reaction time and activity normally increased as a function of delay; these changes were enhanced by FC. The FC-induced decrements in proportion of correct responses suggest a faster loss from short-term memory of both spatial and nonspatial information.

Animals

Fyn signaling in the medial prefrontal cortex regulates resistance to stress-induced object recognition impairments in male rats.

Genome-wide association studies on patients with depression have identified FYN and FYB, an FYN-binding protein, as being linked to depression. We have reported that experimental manipulations in gene expression in the medial prefrontal cortex (mPFC) alter stress-induced object recognition impairments in animals. Therefore, we examined the impact of alterations in FYN and FYB expression in the mPFC of adult male rats on resistance to stress-induced impairments in object recognition. Animals with virus-mediated knockdown or overexpression of Fyn in the mPFC were subjected to either a brief 20-min restraint with 20 intermittent tail shocks, which does not induce object recognition impairment, or a prolonged 60-min restraint with 60 intermittent tail shocks, which does. In an object recognition task, control rats maintained intact object recognition following a brief stress, whereas rats with Fyn knockdown or overexpression in the mPFC showed impaired object recognition. Prolonged stress impaired object recognition in both control rats and rats with Fyn knockdown or overexpression. Additionally, rats with Fyn knockdown in the mPFC exhibited fewer c-Fos-positive cells in the mPFC in response to brief stress, accompanied by a trend toward increased c-Fos in the amygdala compared with control rats. Fyn knockdown also reduced Fyb expression in the mPFC. Furthermore, Fyb knockdown in the mPFC impaired object recognition following brief stress, suggesting that the observed effects are consistent with involvement of a coupled Fyn-Fyb signaling axis rather than Fyn alone. These findings suggest that altered Fyn-related signaling in the mPFC may underlie the resistance to stress-induced object recognition impairments.

Animals

[Interaction between the prefrontal cortex and hippocampus of monkeys in delayed spatial choice].

Interaction between bioelectrical processes in the prefrontal cortex and the hippocampus was investigated on three Macaca mulatta performing a task of delayed spatial choice. It was found that the processes of short-term spatial memory are reflected in certain patterns of reciprocal correlations between EEG of the given structures. Different patterns correspond to tasks of different nature. The data obtained corroborate the hypothesis that the functional significance of brain structures may change instantaneously in the course of mnestic activity, depending on regulation requirements.

Animals

Self-stimulation of the sulcal prefrontal cortex in the rat: direct evidence for ascending dopaminergic mediation.

Intracranial self-stimulation (ICSS) of the prefrontal cortex dorsal to the rhinal sulcus in rats has been abolished by means of injections of 6-hydroxydopamine (6-OHDA) (4 micrograms/2 microliters) into the ascending trajectory of the A10 mesocortical dopaminergic fibers ipsilateral to the stimulation electrodes. Similar injections made contralateral to the stimulation electrodes produced a transient attenuation of this self-stimulation. All cases of such lesions were confirmed with the use of Vibratome histochemical fluorescence examination of each of the dopamine projection areas in the forebrain.

Animals

Synaptic Proteome Divergence in the Prefrontal Cortex of Tame and Aggressive Red Foxes (Vulpes vulpes).

The biological mechanisms behind aggressive and affiliative behaviors are difficult to pinpoint. In the Farm-Fox Experiment, conventional foxes were selectively bred since 1959 in two different directions, one for tame and another for aggressive response to humans. The distinct differences in social behavior of tame, aggressive, and conventional populations are genetically based and the three populations live in conditions that control for factors that could impact social reactions, such as environment and social experiences. Genomic and transcriptomic studies of genetic differences among the fox populations have highlighted genes involved in synaptic processes in the prefrontal cortex. To investigate how the synaptic mechanisms differ between the three fox populations, synaptosomes were isolated from prefrontal and premotor cortex extracts of sixteen female foxes. Tandem mass tags with liquid chromatography tandem mass spectrometry (LC-MS) were used to identify and quantify the relative abundance of the proteins. The results were sorted into protein groups and compared between populations using a limma analysis to determine proteins with differential expression (DE). In the tame versus aggressive comparison, 174 protein groups were found to be DE, while only five were found in the conventional versus aggressive comparison. Most DE protein groups had lower fold expression in the aggressive population compared to tame and aggressive populations. ADGRB2 was found to be the most DE protein group, with 11-fold higher expression in aggressive foxes than in tame foxes. ADGRB2 was previously shown to affect depression-like behavior in mice and is involved in the vascular endothelial growth factor signaling pathway, that is known to influence neurogenesis. Enrichment analyses on the DE protein groups found gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that were enriched in the tame versus aggressive comparison, including multiple, highly enriched terms involving ribosome and translation. Local translation at synapses plays an important role in synaptic plasticity and, as a result, can profoundly influence behavior. This study highlighted potential mechanisms that could underly the behavioral differences between tame and aggressive foxes.

Journal Article

Interhemispheric functional differences in prefrontal cortex of monkeys.

Monkeys had nonpolarizable electrodes implanted bilaterally in prefrontal (principal sulcus), precentral, and occipital cortex. They were trained on a spatial delayed-response (DR) task (8-sec intratrial delay), while cortical potentials were recorded. Three groups of monkeys were trained to 90% criterion: (A) 4 monkeys with only the right hand (the left wrist was attached to the testing chair); (B) 2 monkeys with only the left hand; and (C) 2 monkeys with the left and right hands on alternate sessions. Intermanual transfer tests were then given. Averaged steady potential (SP) shifts of several seconds duration were found in prefrontal cortex during cue presentation and the early portion of the intratrial delay and from the precentral area during the choice response. Evaluations of these SP shift magnitudes indicated: (1) Training with only one hand resulted in substantially larger SP shifts in the prefrontal and precentral areas contralateral to the responding hand; (2) alternate hand training resulted in somewhat larger prefrontal SP shifts in the right hemisphere; (3) intermanual transfer had marked effects on the precentral SP shifts, with larger magnitudes in the hemisphere contralateral to the responding hand, but had little effect on the magnitudes of both prefrontal SP shifts. (4) Subsequent training of Group C monkeys with only one hand resulted in greater SP shifts in the prefrontal area contralateral to the responding hand and in decreased SP shifts in the ipsilateral prefrontal area; and (5) additional intermanual transfer tests had no effects on SP shift magnitudes from both prefrontal areas. These findings indicate a dissociation in interhemispheric functions between the precentral and prefrontal cortical areas, with the formal implicated in motor organization for the contralateral limb, and the latter in mediation of mnemonic processes, primarily in one hemisphere. This hemispheric specialization is affected by the hand-training procedure, but other endogenous or experimential factors may be involved.

Animals