Keith A. Crutcher

Sympathetic sprouting in the central nervous system: a model for studies of axonal growth in the mature mammalian brain

Sympathetic fibers innervate many peripheral tissues but are normally confined to extracerebral structures within the cranial cavity, e.g. blood vessels. The invasion of the central nervous system by vascular sympathetic axons is a unique example of neuronal plasticity which provides new information concerning the regulation and mechanisms of neuronal sprouting in both the peripheral and central nervous systems. In this paper, the principal findings concerning the conditions under which such sprouting occurs, the mechanisms which may be involved, and the question of its possible function are reviewed. Of special interest is the fact that a nerve growth factor-like brain factor may be involved in this growth response. The principles gleaned from studies of this sprouting phenomenon may be applicable to other models of neuronal plasticity and may have clinical relevance.

Medial septal and nucleus basalis magnocellularis lesions produce order memory deficits in rats which mimic symptomatology of Alzheimer's disease.

Rats with electrolytic lesions of the medial septum or ibotenic acid lesions of the nucleus basalis magnocellularis (NBM) were tested in an order memory task for an 8-item list of varying spatial locations within an 8-arm radial maze. Results indicated that rats with small medial septal lesions resulting in small AchE depletion of dorsal hippocampal formation were impaired only for the first, but not the last choice orders of the list. Animals with large medial septal lesions resulting in large AchE depletion of the dorsal hippocampal formation displayed an order memory deficit for all the choice orders of the list. In contrast, rats with small NBM lesions resulting in small AchE depletion of parietal and part of frontal cortex were impaired only for the last, but not the first choice orders of the list. Animals with large NBM lesions resulting in large AchE depletion of parietal and part of frontal cortex displayed an order memory deficit for all the choice orders of the list. The relationship between these findings and mnemonic symptomatology of Alzheimers disease was discussed, as was the possible meaning of these results in providing an animal model for studying certain aspects of the disease.

The septohippocampal projection in the rat: An electron microscopic horseradish peroxidase study

In order to identify the specific targets of the septohippocampal projection in the rat, horseradish peroxidase localization at the electron microscopic level was used. Following injections of free horseradish peroxidase into the medial septum, sections of the dorsal hippocampal formation were reacted with diaminobenzidine and processed for electron microscopy by routine methods. Sections were viewed unstained. Horseradish peroxidase labeling in the dentate gyrus was predominantly in the supra- and infragranular layers. All postsynaptic elements were neuronal. They included granule cell somata and somata and dendrites of hilar cells; these may include pyramidal basket cells. No synaptic contacts with vascular or glial elements were found. These results provide a basis for comparing the specific targets of the septohippocampal projection with those of the sympathohippocampal pathway, which innervates the dentate following lesions of the septohippocampal projection.

Evidence for neocortical involvement in reference memory

Rats were trained on an eight-arm radial maze task using a procedure that provides for an assessment of both working and reference memory. Following training, rats received parietal cortex, medial prefrontal cortex, visual cortex, or nucleus basalis magnocellularis lesions. Rats with visual cortex lesions showed no change in performance on either working or reference memory. Rats with parietal cortex lesions displayed a temporary deficit in reference, but no deficit on working memory. Animals with medial prefrontal cortex lesions showed a temporary deficit on both working and reference memory. Rats with extensive lateral frontal and parietal cortex depletion of acetylcholinesterase following nucleus basalis magnocellularis lesions had a marked disruption only of reference but not of working memory. It is concluded that neocortex and possibly the cholinergic projections to neocortex play an important role in mediating reference memory.

Serial position curves for item (spatial location) information: role of the dorsal hippocampal formation and medial septum

Animals were trained on an item recognition memory task for a list of 5 spatial locations. After reaching criterion performance the animals sustained small or medium-size dorsal hippocampal formation lesions, small or large medial septal lesions, or served as sham-operated or cortical controls. Following recovery from surgery, animals were retested for item recognition memory. Sham-operated and cortical control animals showed no deficits in performance. In contrast, animals with small dorsal hippocampal formation or medial septal lesions displayed a deficit for the early items, but had excellent memory for the last item of the list. Animals with medium-size dorsal hippocampal formation or large medial septal lesions displayed a deficit for both early and late items within the list. Because residual short-term memory capacity can be seen only with small hippocampal formation or medial septal lesions, it is suggested that the hippocampal formation and cholinergic input into the hippocampal formation via the medial septum code spatial information within a continuous extended time frame.

Entorhinal lesions result in increased nerved growth factor-like growth-promoting activity in medium conditioned by hippocampal slices

Nerve growth factor (NGF) is present in high concentrations in the rat hippocampal formation where it may be involved in sympathetic sprouting following septohippocampal denervation. In addition, recent evidence suggests that some forebrain cholinergic neurons, including septohippocampal neurons, are responsive to exogenous NGF. Since septohippocampal neurons have been shown to sprout in response to entorhinal lesions both in rats and, recently, in humans, we sought to determine whether endogenous NGF-like activity increases in the rat hippocampal formation following injury to the entorhinal cortex. We found that entorhinal lesions which result in extensive denervation of the dentate granule cells, and subsequent sprouting of septohippocampal axons, do result in greater NGF-like growth-promoting activity in medium conditioned by slices of the denervated tissue when compared to medium conditioned by control tissue. These results suggest that brain NGF may be involved in injury-induced sprouting of forebrain cholinergic neurons.

Medial septal lesions, radial arm maze performance, and sympathetic sprouting: a study of recovery of function

Long-Evans rats received septal lesions or sham operations and were tested for performance in a radial arm maze, level of activity and water intake in order to test whether recovery of function was mediated by sprouting of peripheral sympathetic fibers. Animals receiving septal lesions displayed an initial deficit in radial arm maze performance followed by recovery. No critical changes occurred in activity level and no recovery was seen in water intake. Subsequent superior cervical ganglionectomies had no effect on recovery of radial arm maze performance. There was a significant relationship between behavioral recovery and the degree of hippocampal AChE depletion. It is concluded that recovery of radial arm maze performance is not mediated by sympathetic sprouting following septal lesions but might be mediated by residual septohippocampal fibers.

Rats with nucleus basalis magnocellularis lesions mimic mnemonic symptomatology observed in patients with dementia of the Alzheimer's type.

College students, healthy elderly subjects, patients diagnosed with mild or moderate dementia of the Alzheimers type, as well as rats with small or large lesions of nucleus basalis magnocellularis (NBM) were tested on an order memory task for a 6- or 8-item list of varying spatial locations. Similar patterns of order memory deficits as a function of serial order position were observed in rats with small or large NBM lesions and patients with mild or moderate dementia of the Alzheimers type. The results provide support for the possibility that rats with NBM lesions might mimic the mnemonic symptomatology of Alzheimers disease.

Equivalent spatial location memory deficits in rats with medial septum or hippocampal formation lesions and patients with dementia of the Alzheimer's type ☆

College students, healthy elderly subjects, patients diagnosed with mild or moderate dementia of the Alzheimers type, as well as rats with small or large lesions of the medial septum (MS), dorsal hippocampal formation (DHF) or nucleus basalis magnocellularis (NBM) were tested on an item memory task for a five- or six-item list of varying spatial locations. Equivalent patterns of item memory deficits as a function of serial order position were observed in rats with small or large MS or DHF lesions and patients with mild or moderate dementia of the Alzheimers type. No deficits were found for NBM-lesioned rats. The results provide support for the possibility that rats with MS and DHF lesions mimic the mnemonic symptomatology of patients with Alzheimers disease.

Memory deficits following nucleus basalis magnocellularis lesions may be mediated through limbic, but not neocortical, targets

In order to test the contribution of the target areas of the nucleus basalis magnocellularis to the mediation of item and order recognition memory for spatial locations, one set of rats received lesions of the dorsolateral frontal cortex, parietal cortex, or basolateral amygdala after training in an order recognition memory task, whereas another set of animals received lesions of the nucleus basalis magnocellularis or basolateral amygdala in an item recognition memory task. Animals with basolateral amygdala lesions displayed a deficit for order recognition memory, but no deficit for item recognition memory, a pattern equivalent to that found for animals with nucleus basalis magnocellularis lesions. In contrast, animals with dorsolateral frontal cortex displayed no deficit, and animals with parietal cortex lesions displayed only a partial deficit for order recognition memory, results that differ from those found for animals with nucleus basalis magnocellularis lesions. It appears that the nucleus basalis magnocellularis influences item and order recognition memory for lists of spatial locations primarily through projections to limbic but not neocortical targets.