Dendritic spine pathology: Cause or consequence of neurological disorders?

The action of thyroid hormones (thyroxine, T4; triiodothyronine, T3) on brain development and function is gaining renewed interest. It has been known for many years that thyroid hormones are very important in mammalian brain maturation, influencing many aspects related to neural cell migration, differentiation, and signaling. In the last 10 years, genes regulated by thyroid hormones have been identified in the rodent brain, and understanding of the role of thyroid hormone nuclear receptors has been facilitated with the analysis of the phenotype of mutant mice for the different receptor isoforms. The general picture that emerges is that T4 and T3 may enter the brain through specific transporters. T4 is converted to the active hormone, T3, in glial cells, astrocytes, and tanycytes, although the main target cells are neurons and maturing oligodendrocytes. T3, acting through the nuclear receptors, controls the expression of genes involved in myelination, cell differentiation, migration, and signaling. In addition to transducing the T3 signal, the nuclear receptors also have activity in the unliganded state (i.e., as aporeceptors), mainly as repressors of transcription. The physiological meaning of aporreceptor action is not known, but they may play a role in the genesis of the hypothyroid phenotype. Among the questions that remain to be explored in more detail is the role of thyroid hormones and the T3 receptors, both liganded and unliganded, in the fetal brain, especially before onset of fetal thyroid gland function. These questions are relevant for human health and the management of thyroid diseases during pregnancy.

Thyroid Hormones and Brain Development

Imbalances in the corticosteroid milieu have been implicated in several neuropsychiatric disorders, including depression and schizophrenia. Prefrontal cortex (PFC) dysfunction is also a hallmark of these conditions, causing impairments in executive functions such as behavioral flexibility and working memory. Recent studies have suggested that the PFC might be influenced by corticosteroids released during stress. To test this possibility, we assessed spatial working memory and behavioral flexibility in rats submitted to chronic adrenalectomy or treatment with corticosterone (25 mg/kg) or the synthetic glucocorticoid dexamethasone (300 μg/kg); the behavioral analysis was complemented by stereological evaluation of the PFC (prelimbic, infralimbic, and anterior cingulate regions), the adjacent retrosplenial and motor cortices, and the hippocampal formation. Dexamethasone treatment resulted in a pronounced impairment in working memory and behavioral flexibility, effects that correlated with neuronal loss and atrophy of layer II of the infralimbic, prelimbic, and cingulate cortices. Exposure to corticosterone produced milder impairments in behavioral flexibility, but not in working memory, and reduced the volume of layer II of all prefrontal areas. Interestingly, adrenalectomy-induced deleterious effects only became apparent on the reverse learning task and were not associated with structural alterations in the PFC. None of the experimental procedures influenced the morphology of retrosplenial or motor cortices, but stereological measurements confirmed previously observed effects of corticosteroids on hippocampal structure. Our results describe, for the first time, that imbalances in the corticosteroid environment can induce degeneration of specific layers of the PFC; these changes appear to be the morphological correlate of corticosteroid-induced impairment of PFC-dependent behavior(s).

https://www.jneurosci.org/content/jneuro/25/34/7792.full.pdf

Morphological Correlates of Corticosteroid-Induced Changes in Prefrontal Cortex-Dependent Behaviors

Chronic stress is a powerful modulator of emotional behaviour. Previous studies have shown that distinct neuronal pathways modulate different emotional behaviours: while the amygdala plays a key role in fear-conditioned-to-cue stimuli, the bed nucleus of stria terminalis (BNST) is implicated in anxiety behaviour and responses to contextual stimuli. In addition, the BNST is directly involved in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis. In the present study, we assessed anxiety (measured in the elevated-plus maze and acoustic startle apparatus) and fear-conditioned responses to light stimuli in rats that had been exposed to either chronic unpredictable stress or corticosterone for 28 days; thereafter, stereological estimates of the BNST and amygdaloid complex were performed, followed by three-dimensional morphometric dendritic analysis. Results show that chronic stress induces hyperanxiety without influencing fear conditioning or locomotion and exploratory activity. Stress-induced hyperanxiety was correlated with increased volumes of the BNST but not of the amygdala. Dendritic remodelling was found to make a significant contribution to the stress-induced increase in BNST volume, primarily due to changes in the anteromedial area of the BNST, an area strongly implicated in emotional behaviour and in the neuroendocrine control of the stress response. Importantly, all of the effects of stress were recapitulated by exogenous corticosterone. In conclusion, this study shows that chronic stress impacts on BNST structure and function; its findings pertain to the modulation of emotional behaviour and the maladaptive response to stress.

Dissociation of the morphological correlates of stress‐induced anxiety and fear

Effects of corticosterone treatment and rehabilitation on the hippocampal formation of neonatal and adult rats. An unbiased stereological study.

We have previously shown that the numerical density of dentate granule and CA3 pyramidal cells of adult rats is reduced after lengthy periods of low-protein diet. In this study, the total number of these neurons was estimated, together with those for the hilar and CA1 pyramidal cells in order to obtain a complete and unbiased insight into the effects of malnutrition and rehabilitation from malnutrition on the structure of the hippocampal formation. Groups of 2-month-old rats were fed a low protein diet (8% casein) for 6, 12 and 18 months and compared with age-matched control and recovery rats. The recovery group was fed a low protein diet for 6 months and then switched to normal diet during the same period. Total numbers of neurons of each hippocampal region were calculated from their numerical density, estimated with the physical disector, and from the volume of the respective cell layers, after correction for the tissue shrinkage factor. The total number of granule, hilar, CA1 and CA3 pyramidal cells was reduced in all groups of malnourished rats including the recovery group. No differences were found between malnourished and recovery groups. These findings indicate that a prolonged low protein diet, started in adult life, leads to a deficit in neuronal numbers in the hippocampal formation, and that it may also disrupt the normal process of cell acquisition in the dentate gyrus. Moreover, our data support the view that the morphological alterations induced by a low protein intake are irreversible.

Effects of long-term malnutrition and rehabilitation on the hippocampal formation of the adult rat. A morphometric study.

In previous quantitative studies we demonstrated that the volumes of the cerebellar and hippocampal granular layers, as well as their total number of cells, were reduced in 30 days old hypothyroid rats. We decided to extend these studies to the prelimbic subarea of the medial prefrontal cortex using the same morphometric procedures. The cortical volume and the total number of neurons of its Layer III were determined. After correcting for the tissue shrinkage factor, it was found that the volume of the entire prelimbic cortex and that of its Layer III was smaller in hypothyroid rats than in controls. Conversely, the number of neurons per unit volume of cortical Layer III was greater in hypothyroids. This indicates that there is a markedly increased cell packing density, probably related to the neuropil impoverishment, as was described by other authors almost forty years ago for the sensorimotor and visual cortices, applying inaccurate quantitative methods.

Estimates of volumes and pyramidal cell numbers in the prelimbic subarea of the prefrontal cortex in experimental hypothyroid rats.

Summary. Abundant ectopic granule cells scattered in the cerebellar molecular layer have been observed in 30day-old hypothyroid rats. Their morphological features indicate that they must be regarded as mature heterotopic cells arrested during their migration towards the granular layer. As their impoverished dendritic trees are identical to those seen in controls, it is unlikely that the lack of thyroid hormones played a major role in the deficient dendritic outgrowth. The study of 180-day-old hypothyroid rats revealed that although ectopic granule cells remained quite numerous, their number per unit surface was lesser than in the 30-day-old hypothyroid group. This finding may be related to the capacity displayed by heterotopic neurons to establish synaptic contacts with the components of the molecular layer. This was inferred by the presente of a peculiar synaptic cell investment formed by axosomatic and somatodendritic contacts in 180-day-old hypothyroid rats which shows that the surviving ectopic granule cells manage to adapt to an adverse milieu.

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Effects of long-term hypothyroidism in the morphology and synaptic organization of cerebellar ectopic granule cells.

Past work showed that chronic alcohol consumption induces massive degeneration in the rat cerebellar cortex. To study the subsequent process of nervous tissue repair, followed itself by a remodelling activity, groups of alcohol-treated rats for 3 and 6 months were used and the results compared with the respective age-matched controls. From the wide variety of cells which display phagocytic activity in the mammalian brain it was found, based on qualitative observations, that two types were clearly involved in the removal of the alcohol-induced degenerated debris: the resident microglial cells and the non-resident brain macrophages. This assumption was corroborated by the study of their origin, using carbon particles and latex beeds intravenously injected, which showed that brain macrophages were the sole population to be labelled. These observations fit with the multiple origin concept for neural phagocytosis which postulates that different cell types can be recruited for the removal of the damaged neural tissue depending on the severity of the lesions and on the extension of the blood vessels damage.

Madeira

Papers

Effects of long-term malnutrition and rehabilitation on the hippocampal formation of the adult rat. A morphometric study.

Estimates of volumes and pyramidal cell numbers in the prelimbic subarea of the prefrontal cortex in experimental hypothyroid rats.

Effects of long-term hypothyroidism in the morphology and synaptic organization of cerebellar ectopic granule cells.

Blood-derived phagocytes in the cerebellar cortex of the rat after chronic alcohol consumption.