Jesper Mogensen

The Prefrontal 'Cortex' in the Pigeon

In3 pigeons ablation of the posterodorsolateral neostriatum impaired delayed alternation without affecting visual discrimination. In mammals the same selective deficit is produced by lesions in the prefrontal system. The presently ablated neostriatal region resembles the mammalian prefrontal cortex also by being richly innervated with dopaminergic fibers. This region is clearly separated from paleostriatum augmentatum and archistriatum which also have a strong dopaminergic innervation. The presence of a prefrontal cortex-like formation in a bird species raises the possibility that all higher vertebrates are equipped with this neural device.

The prefrontal ‘cortex’ in the pigeon. Biochemical evidence☆

Concentrations of dopamine and noradrenaline were determined in 6 regions of the telencephalon and in the cerebellum of the pigeon. Noradrenaline was rather evenly distributed. A significant variation was found of the dopamine-noradrenaline ratio (DA:NA), a measure which makes it possible to distinguish dopamine found in dopaminergic fibers from dopamine which is precursor of noradrenaline. The highest ratio was found in the anteroventromedial region (containing the presumed homologue of the mammalian neostriatum), and the next highest in the posteroventrolateral region (containing the archistriatum). Like in mammals, the lowest concentration of the non-precursor dopamine in the pigeon brain seems to be contained in the cerebellum. Among the regions which show physiological and anatomical similarities with the mammalian cerebral cortex, the DA:NA ratio was significantly higher in the posterodorsolateral, than in the posterodorsomedial and anterodorsomedial regions. The two dorsomedial regions contain the equivalents of the hippocampus and sensory cortical areas of mammals. The strong dopamine innervation of the posterodorsolateral region is comparable to that of the mammalian prefrontal cortex.

Erythropoietin improves place learning in fimbria-fornix-transected rats and modifies the search pattern of normal rats.

The acquisition of a water-maze-based allocentric place learning task was studied in four groups of rats: two groups subjected to bilateral transections of the fimbria-fornix and two groups undergoing a sham control operation. At the moment of surgery all animals were given one systemic (intraperitoneal) injection of either human recombinant erythropoietin (EPO) (at a dosage of 5000 IU/kg body weight), given to one of the fimbria-fornix-transected groups and one of the sham-operated groups, or vehicle (saline), given to the two remaining groups. The 25-day task acquisition period (one session/day) began 6 or 7 days after the day of surgery. The fimbria-fornix-transected and saline-injected group exhibited a pronounced and long-lasting impairment of task acquisition. In contrast, the fimbria-fornix-transected and EPO-treated group demonstrated a less pronounced and more transient lesion-associated impairment. The two sham-operated groups did not differ with respect to the proficiency of task acquisition. But administration of EPO to intact animals caused a significant modification of swim patterns-apparently reflecting a somewhat modified strategy of task solution. It is concluded that systemic administration of EPO significantly improves the posttraumatic functional recovery of the presently studied place learning task after transections of the fimbria-fornix. Additionally, administration of EPO influences the strategy, although not quality, of task solution in normal (sham-operated) rats.

Long-term retrograde labelling of neurons

The intensity of labelling of neuronal perikarya with Fluoro-gold or rhodamine microspheres appeared unchanged in rats surviving one year after surgery. These tracers may be used for sequential labelling with long intervals and to study brain connections in precious specimens.

Place learning and object recognition by rats subjected to transection of the fimbria-fornix and/or ablation of the prefrontal cortex

The acquisition of a water maze-based allocentric place learning task and an exploration based object recognition task were studied in four groups of rats: animals in which the fimbria-fornix had been transected, rats who had received bilateral ablations of the anteromedial prefrontal cortex, animals in which both of these structures had been lesioned, and a sham operated control group. None of the groups showed impairments of object recognition. Ablations of the prefrontal cortex caused a mild impairment in the acquisition of the place learning task. The two fimbria-fornix transected groups exhibited a severe impairment during the acquisition of this task. All groups reached criterion level task performance eventually. All groups were subjected to a number of behavioural and pharmacological challenges in order to elucidate the neural and cognitive mechanisms of this behavioural recovery. During a no-platform session both the fimbria-fornix transected group and the prefrontally ablated group demonstrated a normal preference for the former platform position. The combined lesion group, however, failed to show a similar preference for this position. The outcome of the pharmacological challenges demonstrated that while the task performance of all four groups relied equally on catecholaminergic mediation, only the task solution of the fimbria-fornix transected group was significantly impaired by disturbance of the catecholaminergic systems. The data indicated a high likelihood that prefrontal cortical mechanisms contribute to the recovery of allocentric place learning after fimbria-fornix transections.

Prefrontal cortex and hippocampus in posttraumatic functional recovery: Spatial delayed alternation by rats subjected to transection of the fimbria–fornix and/or ablation of the prefrontal cortex

Lesions of the prefrontal cortex and the hippocampus often lead to impairment of the same behavioural tasks (e.g., allocentric as well as egocentric spatial orientation and spatial delayed alternation). In case of allocentric and egocentric spatial orientation we have previously found that the two structures mutually contribute to the posttraumatic functional recovery of such tasks. We therefore presently tested the hypothesis that this would even be true in case of spatial delayed alternation. The acquisition of a spatial delayed alternation task in a T-maze was studied in four groups of rats: animals in which the fimbria-fornix had been transected bilaterally, rats who had received bilateral ablations of the anteromedial prefrontal cortex, animals in which both of these structures had been lesioned, and a sham operated control group. All three lesion groups demonstrated an impaired task acquisition. The group given prefrontal cortical lesions in isolation underwent a complete functional recovery. Both of the fimbria-fornix transected groups were significantly impaired even when compared to the group given prefrontal cortical ablations in isolation. The two fimbria-fornix lesioned groups did, however, exhibit levels of functional recovery. The group in which both structures had been lesioned demonstrated a task acquisition, which was significantly inferior to that of the group given fimbria-fornix transections in isolation. After completion of the task acquisition period, all animals were subjected to two behavioural challenges including a session on which the duration of the inter-trial delay was doubled. This expansion of the inter-trial delay rather selectively impaired the task performance of the group given fimbria-fornix transections in isolation. Consequently, both during the acquisition period and in one of the challenges a differentiation of functional recovery was seen between the combined lesioned group and the group given fimbria-fornix lesions only. This indicates that even in case of a spatial delayed alternation task the prefrontal cortex normally contributes significantly to mediation of posttraumatic functional recovery after isolated lesions of the fimbria-fornix. The results are discussed in the context of models of posttraumatic functional recovery.

Vertical ascending connections in the isocortex

SummaryDifferent fluorescent tracers were applied to the surface of the cortex of rats, marmosets and one hedgehog. Irrespective of the kind of tracer and the depth of penetration, some perikarya of layer VI were labelled in each specimen and in all cortical regions. In the rat almost all labelled neurons were packed in sublayer VIb, in the marmoset such cells were dispersed throughout layer VI, whereas in the bedgehog the degree of their segregation to sublayer VIb was intermediate. Additional experiments in the rat indicated that most of the medium-sized neurons in the VIb layer project to layer I, that most of the perikarya projecting to the thalamus are localized in sublayer VIa, that different neurons project to the thalamus and to the surface of the cortex, and that only very few perikarya in deep parts of layers III and V and of sublayer VIa send axons or axon collaterals to layers I and II.

Sequential behavior after modified prefrontallesions in the rat

Ablation of the “orbital” prefrontal area, which includes the dorsal bank of the rostral third of the rhinal sulcus and the ventral surface of the frontal pole, strongly impaired performance of a new task that required sequential manipulation of two different and spatially distant manipulanda. Performance of the same task was only mildly, but significantly, affected by dorsomedial prefrontallesions. The two groups did not significantly differ from sham-operated controls in the rate of barpressing for continuous reinforcement, in extinction of two operant responses, or in spontaneous alternation. Unexpectedly, the present variant of sequential behavior was more affected by the “orbital” prefrontallesion than by the lesions of the cortex, which, in the rat, combines the medial prefrontal cortex and anterior cingulate areas and has been considered to be involved in the sequencing of behavioral chains.

Reorganization of the injured brain: implications for studies of the neural substrate of cognition.

In the search for a neural substrate of cognitive processes, a frequently utilized method is the scrutiny of post-traumatic symptoms exhibited by individuals suffering focal injury to the brain. For instance, the presence or absence of conscious awareness within a particular domain may, combined with knowledge of which regions of the brain have been injured, provide important data in the search for neural correlates of consciousness. Like all studies addressing the consequences of brain injury, however, such research has to face the fact that in most cases, post-traumatic impairments are accompanied by a “functional recovery” during which symptoms are reduced or eliminated. The apparent contradiction between localization and recovery, respectively, of functions constitutes a problem to almost all aspects of cognitive neuroscience. Several lines of investigation indicate that although the brain remains highly plastic throughout life, the post-traumatic plasticity does not recreate a copy of the neural mechanisms lost to injury. Instead, the uninjured parts of the brain are functionally reorganized in a manner which – in spite of not recreating the basic information processing lost to injury – is able to allow a more or less complete return of the surface phenomena (including manifestations of consciousness) originally impaired by the trauma. A novel model [the Reorganization of Elementary Functions-model] of these processes is presented – and some of its implications discussed relative to studies of the neural substrates of cognition and consciousness.

Erythropoietin Improves Place Learning in an 8-Arm Radial Maze in Fimbria-Fornix Transected Rats

Systemically administered human recombinant erythropoietin (EPO) may have the potential to reduce the cognitive and behavioral symptoms of mechanical brain injury. In a series of studies, we address this possibility. We previously found that EPO given to fimbriafornix transected rats at the moment of injury could substantially improve the posttraumatic acquisition of an allocentric place learning task when such a task is administered in a water maze. Due to the clinical importance of such results, it is important to scrutinize whether the therapeutic effect of EPO is specific to the experimental setup of our original experiments or generalizes across test situations. Consequently, here we studied the effects of similarly administered EPO in fimbria-fornix transected and control operated rats, respectively, evaluating the posttraumatic behavioral/cognitive abilities in an allocentric place learning task administered in an 8-arm radial maze. The administration of EPO to the hippocampally injured rats was associated with a virtually complete elimination of the otherwise severe behavioral impairment caused by fimbria-fornix transection. In contrast, EPO had no detectable effect on the task acquisition of non-lesioned animals. The results of the present study confirm our previous demonstration of EPOs ability to reduce or eliminate the behavioral/cognitive consequences of mechanical injury to the hippocampus, while adding the important observation that such a therapeutic effect is not restricted to the specific experimental setup previously studied.