ter Gert Horst

The course of paraventricular hypothalamic efferents to autonomic structures in medulla and spinal cord

By application of the anterograde transport technique of Phaseolus vulgaris leuco-agglutinin the descending autonomic projection of the paraventricular hypothalamic nucleus was investigated. The Phaseolus lectin technique allowed the detection of the cells of origin in the paraventricular PVN, the precise position of two distinct descending axon pathways and the detailed morphology of terminal structures in midbrain, medulla oblongata and spinal cord.

The Hypothalamus, Intrinsic Connections and Outflow Pathways to the Endocrine System in Relation to the Control of Feeding and Metabolism

Abbreviations

Descending pathways from hypothalamus to dorsal motor vagus and ambiguus nuclei in the rat

The anatomical pathways between the hypothalamus and cell groups of the lower medulla that are involved in the neural control of endocrine pancreas activity were investigated. As part of this control system the descending pathways originating from lateral, dorsomedial and ventromedial hypothalamic nuclei towards the dorsal motor vagus and ambiguus nuclei, were studied by retrograde transport of horseradish peroxidase. Very small injections of the tracer, by means of the iontophoretic delivery method, were placed in the dorsal motor vagus, ambiguus and solitary tract nucleus as well as in the various nuclei of the medullary reticular formation. Subsequent retrograde labeling was studied in the hypothalamus and the brainstem. The appearance of considerable retrograde labeling in mesencephalic periventricular grey and rostral mesencephalic reticular formation indicated a possible role for these structures as intermediates in an indirect hypothalamo-medullary control circuitry. This led us to extend the peroxidase injections to these mesencephalic areas after which the hypothalamus was investigated for retrograde labeling. All data combined indicated the existence of three descending pathways, direct and indirect, between hypothalamus and the parasympathetic motor nuclei of the lower medulla.

Phaseolus vulgaris Leuco-Agglutinin Tracing of Intrahypothalamic Connections of the Lateral, Ventromedial, Dorsomedial and Paraventricular Hypothalamic Nuclei in the Rat

Intrahypothalamic connections of the lateral (LHA), ventromedial (VMH), dorsomedial (DMH) and paraventricular (PVN) hypothalamic nuclei were studied with anterograde transport of iontophoretically injected Phaseolus vulgaris leuco-agglutinin and the immunocytochemical detection of labeled structures. The LHA was found to give rise to a minor projection in the VMH, whereas the VMH in reverse maintains few connections with the ventromedial part of the tuberal LHA. Tracer deposits in both the LHA and VMH resulted in anterograde terminal labeling in the DMH. The DMH, in turn, donates a small number of projections to the LHA and VMH. The main projection of the DMH is aimed at the parvocellular paraventricular nucleus. Direct outflow pathways from the VMH to the PVN were not found, but lectin injections in the LHA on the other hand gave rise to terminal labeling in both the parvocellular and magnocellular divisions of the PVN. The PVN in turn was found to give only minor reciprocal projections to the LHA, DMH and VMH. These findings indicate that the main stream of connections in the hypothalamus runs from the LHA and VMH to the DMH, and from the DMH to the PVN. The identified circuitry patterns were discussed with respect to the role of the hypothalamus in the control of homeostasis and metabolic regulation, and more specifically in relation to the modulation of the hormone release from the pancreas and adrenal glands.

Migraine and function of the immune system: a meta-analysis of clinical literature published between 1966 and 1999

Mechanisms underlying migraine precipitation are largely unknown. A role of the immune system in migraine precipitation is a matter of debate because of the association of atopic disorders and migraine. Recently, it was demonstrated that migraineurs benefit from eradication of a Helicobacter pylori infection, which substantiates a possible role for (sub-clinical) infections in precipitation of migraine. Since 1966, about 45 clinical investigations have reported on alterations of immune function in migraine patients, which we present in this review. Changes of serum levels of complement and immunoglobulins, histamine, cytokines and immune cells were found in some of these studies but in most cases not corroborated by others. Migraineurs suffering from comorbid atopic disorders show elevated plasma IgE levels but not patients without a type I hypersensitivity. Histamine plasma levels are chronically elevated in migraineurs, and interictally decreased lymphocyte phagocytotic function and increased plasma tumor necrosis factor alpha (TNFα) levels were found, and may be related to increased infection susceptibility. The cause of this increased susceptibility is unclear but most likely is a result of chronic stress, a well-known suppressor of the immune system. Stress relief enhances immune activity and triggers a burst of circulating vasoactive compounds that function as mediators of inflammation and potential precipitators of a migraine attack in vulnerable subjects. In conclusion, in the clinical literature of the past decades, there is no clear-cut evidence of an immune dysfunction in migraineurs, but we cannot totally exclude the possibility of an altered immune function in migraineurs. Discrepancies in the literature most likely are caused by the divergent patterns of sample collection relative to the time of the attack. We propose stringent definition of sample collection times for future studies of immune function in migraine patients.

Molecular correlates of impaired prefrontal plasticity in response to chronic stress.

Disturbed adaptations at the molecular and cellular levels following stress could represent compromised neural plasticity that contributes to the pathophysiology of stress‐induced disorders. Evidence illustrates atrophy and cell death of stress‐vulnerable neurones in the prefrontal cortex. Reduced plasticity may be realized through the destabilized function of selective proteins involved in organizing the neuronal skeleton and translating neurotrophic signals. To elucidate the mechanisms underlying these effects, rats were exposed to chronic footshock stress. Patterns of c‐fos, phospho‐extracellular‐regulated protein kinases 1/2 (ERK1/2), calcineurin and phospho‐cyclic‐AMP response‐element binding protein (CREB) expression were subsequently investigated. The results indicate chronic stress‐induced impairments in prefrontal and cingulate signal transduction cascades underlying neuronal plasticity. The medial prefrontal cortex, demonstrated functional hyperactivity and dendritic phospho‐ERK1/2 hyperphosphorylation, while reduced c‐fos and calcineurin immunoreactivity occurred in the cingulate cortex. Significantly reduced phospho‐CREB expression in both cortical regions, considering its implication in brain‐derived neurotrophic factor (BDNF) transcription, suggests reduced synaptic plasticity. This data confirms the damaging effect of stress on cortical activity, on a molecular level. Due to the association of these markers in the regulation of BDNF signalling, these findings suggest a central role for intracellular neurotrophin transduction members in the pathways underlying cellular actions of stress in the brain.

Unique patterns of FOS, phospho-CREB and BrdU immunoreactivity in the female rat brain following chronic stress and citalopram treatment

Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined. Here we show that chronic footshock stress (21 days) promotes HPA axis hyperactivity (as seen by the increased FOS-ir in the paraventricular hypothalamic nucleus (PVN), plasma corticosterone and adrenal hypertrophy), reduces hippocampal BrdU immunoreactivity and suppresses cortical-limbic CREB phosphorylation in female rats. Long-term citalopram treatment, in contrast, attenuates stress-induced elevation of corticosterone levels and adrenal hypertrophy, although it does not reverse footshock-mediated induction of FOS-ir in the PVN, inhibition of CREB phosphorylation and reduction of hippocampal BrdU-labeling. Moreover, citalopram administration was also associated with significant hypophagic effects and inhibition of CREB phosphorylation. These data suggest that, in female rats, normalization of chronic stress-induced HPA axis abnormalities may represent an initial phase of citalopram-mediated therapeutic actions and despite this SSRIs apparent lack of effects on neuroplasticity, we cannot exclude the possibility that some neurochemical adaptations occur in a later stage which may require more than 3 weeks of treatment to manifest.

Gender-specific effects of social housing on chronic stress-induced limbic Fos expression.

Stress plays an important role in the development of affective disorders. Women show a higher prevalence for these disorders then men. The course of a depressive episode is thought to be positively influenced by social support. We have used a chronic mild stress model in which rats received footshocks daily for 3 weeks. Since rats are social animals we hypothesised that social housing, as a possible model for human social support, might reduce the adverse effects of chronic stress. Brain activity after chronic stress was measured in several limbic brain areas with the neuronal activation marker c-fos. High behavioural activity due to housing rats under reversed light-dark conditions could be responsible for the observed high within group variability in some limbic regions. FOS- (ir) in the paraventricular nucleus of the hypothalamus (PVN) was increased in all stress-exposed groups, except for the socially housed females who showed increased FOS-ir in control condition. Individually housed males and socially housed females showed increased FOS-ir in the dorsal raphe (DRN). Amygdala nuclei were differentially affected by stress, gender and housing conditions. Also the mesolimbic dopaminergic system showed gender specific responses to stress and housing conditions. These results indicate that social support can enhance stress coping in female rats, whereas in males rats, group housing appears to increase the adverse effects of chronic stress, although the neurobiological mechanism is not simply a reduction or enhancement of stress-induced brain activation.

Future antidepressants: what is in the pipeline and what is missing?

Monoamine reuptake inhibitors still reign in the treatment of major depression, but possibly not for long. While medicinal chemists have been able to reduce the side effects of these drugs, their delayed onset of action and considerable non-response rate remain problematic. Of late, serious questions have been raised regarding the efficacy of monoamine reuptake inhibitors.The present review presents an inventory of what is (and until recently was) in the antidepressant pipeline of pharmaceutical companies. Novel antidepressant compounds can be categorised into four groups depending on their target(s): (i) monoamine receptors; (ii) non-monoamine receptors; (iii) neuropeptide receptors; and (iv) hormone receptors. Other possible targets include components of post-receptor intracellular processes and elements of the immune system; to date, however, compounds specifically aimed at these targets have not been the subject of clinical trials.Development of several compounds targeted at monoamine receptors has recently been discontinued. At least five neurokinin-1 (NK1) receptor antagonists were until recently in phase II of clinical testing. However, the apparent interest in the NK1 receptor should not be interpreted as representing a departure from the monoamine hypothesis since neurokinins also modulate monoaminergic systems.In the authors’ view, development of future antidepressants will continue to rely on the serendipity-based monoamine hypothesis. However, an alternative approach, based on the hypothesis that chronic stress precipitates depressive symptoms, might be more productive. Unfortunately, clinical results using drugs targeted at components of the HPA axis have not been very encouraging to date. In the short run, the authors believe that augmentation strategies offer the best hope for improving the efficacy of antidepressant treatment. Several approaches to improve the efficacy of SSRIs are conceivable, such as concurrent blockade of monoamine autoreceptors and the addition of antipsychotics, neuromodulators or hormones (HPA axis and gender related). In the long-term, however, construction of a scientifically verified conceptual framework will be needed before more effective antidepressants can be developed. It can be argued that it is not depression itself that should be treated, but rather that its duration should be reduced by pharmacological means. Animal models that take this concept into consideration and identify mechanisms for acceleration of recovery from the effects of stress need to be developed.

Immunohistochemical changes induced by repeated footshock stress: revelations of gender-based differences

As a growing literature has proven, adverse experiences, particularly when severe and persistent, play a pivotal role in the development of neuronal dysfunctions and psychopathology. In the present study, the neurochemical changes induced by acute and repeated footshock exposure were investigated at the molecular and cellular level, using c-fos and phospho-ERK1/2 immunoreactivity and gene expression arrays. Marked gender-related differences were found following both acute and prolonged footshock exposure. Acute aversive conditioning resulted in significant immunohistochemical changes that might be critically involved in the modulation of fear-related responses, especially in males. Prolonged footshock exposure, on the contrary, was associated with sustained hypothalamic-pituitary-adrenal axis hyperactivity, differential gender-related patterns of cortical-limbic activity, and abnormal neuronal plasticity, especially in medial prefrontocortical regions. These data may provide additional insights into the understanding of the neural circuits underlying the effects of acute and repeated footshock exposure as well as clarify some of the mechanisms involved in the development of stress-related neuronal abnormalities.