Isao Kitayama

Long-Term Stress Degenerates, But Imipramine Regenerates, Noradrenergic Axons in the Rat Cerebral Cortex

Exposed to a forced walking stress for 2 weeks, some rats became persistently inactive (depression-model rats), whereas others gradually recovered from exhaustion (spontaneous recovery rats). We also studied rats exposed to short-term stress, rats without stress, and the model rats treated with imipramine or saline. We examined the density of noradrenergic axons in the frontal cortex using retrograde labeling of the locus coeruleus with horseradish peroxidase injected into the cortex and immunohistochemical staining of cortical axons with dopamine beta-hydroxylase antiserum. The density was significantly lower in the depression-model rats, but tended to be higher in the recovery rats and short-term stressed rats. Chronic treatment with imipramine significantly increased the density in the model rats. There was also a correlation between the density of noradrenergic axons and the recovery rate of activity. Our results suggest that cortical noradrenergic degeneration is involved in the pathogenesis of depression.

DEGENERATION OF LOCUS COERULEUS AXONS IN STRESS-INDUCED DEPRESSION MODEL

Antidepressants such as desipramine induce axonal regeneration of brain noradrenergic neurons. This novel action of antidepressants suggests the involvement of degeneration or retraction of brain noradrenergic axons in the pathophysiology of clinical depression. The present study was designed to further confirm this view in an animal model of stress-induced depression. The depression model was produced by exposing rats to prolonged forced walking stress. To see if axonal degeneration of noradrenergic neurons occurred in the depression model, the density of noradrenergic axons in the cerebral cortex was assessed by three different methods, antidromic stimulation technique, retrograde tracing with horseradish peroxidase and immunohistochemical staining with dopamine-beta-hydroxylase antiserum. These methods all assured of degenerative changes of noradrenergic axon terminals in the depression model. Furthermore, it was found that repeated treatments of the depression-model rats with imipramine could cause regeneration of cortical noradrenergic axons. These findings support the view that degeneration or retraction of noradrenergic axons is involved in the pathophysiology of depression.

Clinical and experimental studies on the pathogenesis of depression.

Abstract (1) Serum TSH responses to TRH showed abnormal patterns in terms of diminished, delayed and exaggerated responses in more than one third of the depressed patients. (2) These findings suggest the pathogenetic importance of the hypothalamo-pituitary dysfunction in depressed patients. Because of this, a number of patients, especially those with diminished and delayed TSH responses to TRH, are prone to develop latent hypothyroidism which might make them resistant to antidepressants. (3) To elucidate the underlying mechanism of these clinical findings, changes in brain monoamines of ‘depression model rats’ were examined by the histochemical fluorescence method. (4) Fluorescence intensity in nerve cells of the ascending NA system (A1, A2, A5, A6, A7) was markedly increased and fluorescence intensity in cell bodies (A12) and nerve terminals (ext. ME) of the tubero-infundibular DA system was decreased.

Psychoendocrine model of depression

Abstract (1) Hypothalamo-pituitary dysfunction appears to be the most significant finding of neuroendocrine studies of depression. (2) The underlying pathology of this dysfunction is probably a metabolic disturbance of brain monoamines. (3) Brain monoamines were examined by the fluorescence histochemical method in a stress-induced animal model of depression. (4) An increase in fluorescence intensity was found in the cell groups of the ascending NA system. (5) Cell bodies and nerve terminals of the tubero-infundibular DA system showed a decrease of fluorescence intensity. (6) The turnover rate of catecholamines in nerve terminals of the ascending NA system decreased.

Increased expression of magnocellular arginine vasopressin mRNA in paraventricular nucleus of stress-induced depression-model rats.

Exposure of rats to long-term intermittent walking stress results in a persistent inactive behavior in the subsequent two weeks in about 50% of rats (depression-model rats) while the activity returns gradually toward baseline in other rats (spontaneous recovery rats). To explore the role of hypothalamic-pituitary-adrenal (HPA) axis in these depression-model rats, we examined changes in the gene expression of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) in the paraventricular nucleus (PVN) of the hypothalamus using in situ hybridization histochemistry. We imposed the intermittent walking stress for two weeks in male Wistar rats, then compared the response of the depression-model rats and spontaneous recovery rats. The expression of CRF mRNA in PVN increased significantly by 60% and 80% compared to controls, in the model and the recovery rats, respectively. The magnocellular AVP mRNA in PVN increased significantly in the model rats by 60% compared to controls. The concentration of plasma ACTH increased in the model rats, but no significant change in plasma corticosterone or AVP level was noted in all three groups. Our results suggest that increased magnocellular AVP in PVN plays an important role in the regulation of HPA axis of the depression-model rats induced by long-term walking stress.

TYROSINE HYDROXYLASE ACTIVITY IN DISCRETE BRAIN REGIONS OF DEPRESSION MODEL RATS

Abstract: Tyrosine hydroxylase (TH) activity was measured in discrete brain regions of rats during short‐term forced running stress (FRS). TH activity was also determined in a depression‐like state and in a recovered state after a long‐term FRS. Under the short‐term FRS, the TH activity showed a significant increase in the locus ceruleus, certain limbic regions and tuberoinfundibular system. In the depression‐like state, however, there was a significant decrease in the locus ceruleus and certain limbic regions, but a significant increase was seen in the median eminence. The TH activity in recovered rats showed no difference from the level in the controls. These findings demonstrate an adaptive increase in the TH activity in relation to stress, and may also indicate a failure of adaptation in the depression‐like state.

DECREASED EXPRESSION OF THE MRNA FOR SOMATOSTATIN IN THE PERIVENTRICULAR NUCLEUS OF DEPRESSION-MODEL RATS

Expression of the mRNA for somatostatin (SRIF) in the periventricular nucleus (PeN), the level of SRIF in the stalk-median eminence (SME) and the concentration of growth hormone (GH) in the plasma were examined in depression-model rats in an attempt to confirm the hypothesis that SRIF neurons in the hypothalamus are hypofunctional in this model. We exposed male Wistar rats to intermittent walking stress for two weeks and then we measured their spontaneous running activity for 12 days. We divided the rats into a depression-model group and a partial-recovery group according to the spontaneous running activity of each rat after the termination of exposure to stress. Expression of SRIF mRNA in the PeN of the hypothalamus was monitored by in situ hybridization and relative levels were determined with an image analysis system. The relative level of expression of SRIF mRNA in the PeN was lower in rats in the depression-model group than in the control group and the partial-recovery group. The level of SRIF in the SME was lower and the plasma concentration of GH was higher in the depression-model group than in the other groups. Our findings suggest that reduced expression of mRNA for SRIF in the PeN might be associated with the pathophysiology of rats with this particular model of depression.

Changes of Brain Monoamines in the Animal Model for Depression

Depression is the most fundamental psychosomatic reaction caused by various etiological factors of which some are known to be genetic, some are environmental, and some are of physical nature. The essence of depression, regardless of etiology, is a reduction of vital potency which is directly manifested by symptoms such as depressed mood, retardation of the psychic process, decrease of individual drives and general activity, and impairment of basic biological rhythms. On the basis of these fundamental symptoms, various kinds of individual personality reactions, namely self-depreciation, self-reproach, pessimistic thinking, hypochondriacal preoccupation, phobia, depersonalization and so on, can develop and make up diverse clinical pictures. Despite the variety of its clinical manifestations, depression is the most therapeutically accessible state by such biological treatments as antidepressants or electroconvulsive therapy. Accordingly, it may be indisputable that the basic symptoms of depression are brought about through a final common biological pathway irrespective of etiology.

Contribution of the stress-induced degeneration of the locus coeruleus noradrenergic neurons to the pathophysiology of depression: a study on an animal model.

A novel theory on the pathophysiology of depression would be expected to resolve a contradiction between therapeutic time lag and monoamine hypothesis. On the basis of the fact that a subgroup of depression appears during or after stress, we exposed rats to a long-term (2 weeks) forced walking stress and produced depression-model rats in one group and spontaneous recovery rats in another. The density of axon terminals of the locus coeruleus (LC) neurons in the frontal cortex stained by dopamine β-hydroxylase antiserum was lower in the depression-model rats than in the spontaneous recovery rats and in the control rats without stress. The density was higher in the model rats daily treated with imipramine than in those treated with saline. Morphological projection (MP) index (a percentage of horseradish peroxidase-positive LC cells in total number of LC cells) and electrophysiological projection index (a percentage of LC neurons activated antidromically by electrical stimulation of the cerebral cortex) were lower in the depression-model rats than in the recovery and control rats. MP index was higher in the imipramine-treated rats than that in the saline-treated rats. Electron microscopic examination of the LC disclosed such degenerative changes as low-dense areas without structure, aggregation of intracellular organs, destroyed membranes around the rough endoplasmic reticulum (rER), a decreased number of deformed subsurface cisterns, glia invaginated into the LC neurons and prominent appearance of microglia containing increased number of lipofustin or lysosome in the model rats, but not in the spontaneous recovery rats. These findings suggest that the terminals and cell bodies of the LC noradrenergic neurons degenerate in the stress-induced depression-model rats and regenerate in the imipramine-treated model rats. This degenerative change may possibly contribute to the decrease in synthesis and metabolism of noradrenaline (NA), the slowing of axonal flow, the accumulation of NA in the neurons, the decrease in discharge rate of LC neurons without stress and the increase in release of NA in response to an additional stress. It may also explain the therapeutic time lag that is required to repair the noradrenergic neurons.

Pure Word Deafness with Possible Transfer of Language Dominance

Abstract: A 55‐year‐old, right‐handed male patient wtih a past history of a stroke followed by a difficulty of speech and hearing fell and manifested a left hemiplegia. He could neither comprehend spoken language and melody nor repeat them, though he spoke with paraphasia and understood written language and nonverbal sound. An electroencephalogram, pneumoencephalogram and cerebral angiogram suggested the existence of old infarcts in the left temporal lobe and a probable new one in the right cerebrum. A diagnosis of this case was made as pure word deafness which might be caused by a reimpairment of the language function possibly transferred to the nondominant, right hemisphere following the early stroke.