Konstantinos Kalafatakis

Structural and functional alterations in the hippocampus due to hypothyroidism

Thyroid hormones (THs) exert a broad spectrum of effects on the central nervous system (CNS). Hypothyroidism, especially during CNS development, can lead to structural and functional changes (mostly resulting in mental retardation). The hippocampus is considered as one of the most important CNS structures, while the investigation and understanding of its direct and indirect interactions with the THs could provide crucial information on the neurobiological basis of the (frequently-faced in clinical practice) hypothyroidism-induced mental retardation and neurobehavioral dysfunction. THs-deficiency during the fetal and/or the neonatal period produces deleterious effects for neural growth and development (such as reduced synaptic connectivity, delayed myelination, disturbed neuronal migration, deranged axonal projections, decreased synaptogenesis and alterations in neurotransmitters’ levels). On the other hand, the adult-onset thyroid dysfunction is usually associated with neurological and behavioural abnormalities. In both cases, genomic and proteomic changes seem to occur. The aim of this review is to provide an up-to-date synopsis of the available knowledge regarding the aforementioned alterations that take place in the hippocampus due to fetal-, neonatal- or adult-onset hypothyroidism.

Contribution of neurotensin in the immune and neuroendocrine modulation of normal and abnormal enteric function

Among various hormones, which are synthesized by intestinal cells and influence enteric function, neurotensin (NT) has gained scientific attention the last three decades. This neuropeptide, mainly located in neuronal synaptic vesicles of hypothalamus and in neuroendocrine cells of the small bowel, participates in enteric digestive processes, gut motility and intestinal inflammatory mechanisms by cooperating with other regulators such as histamine, substance P and somatostatin. NT plays an important role mainly in intestinal lipid metabolism by cooperating with cholecystokinin and establishes a hormonal brain-gut-adipose tissue connection, which could adjust appetite, weight status and generally eating behavior with the amount and the content (particularly fat) of food intake. Moreover, NT achieves a multi-level control of intestinal motility by cooperating with the enteric- and central nervous system, and other enteric hormones (such as somatostatin). NT regulates motility patterns related to the efficiency of the digestive process, stool emptying, transition from the fasted to the postprandial state and reestablishment of the fasted status. In addition, NT possesses a long-term enteroprotective role towards the intestinal tract, despite the fact that under certain circumstances NT may participate in short-term subcellular pathways promoting an acute inflammatory response. The aim of this review is two-fold. First, is to provide an up-to-date synopsis of the available knowledge regarding the involvement of neurotensin in enteric functional status, and highlight its significance in physiological and pathological conditions. Second, is to propose new research directions concerning the role of neurotensin and other intestinal regulatory peptides in the establishment of the brain-gut axis and in the development of functional disorders of the abdominal tract. Conclusively, to clarify the areas, in which an experimental therapeutic intervention, based on NT analogs, may lead to encouraging results.

The Importance of Biological Oscillators for Hypothalamic-Pituitary-Adrenal Activity and Tissue Glucocorticoid Response: Coordinating Stress and Neurobehavioural Adaptation

The hypothalamic‐pituitary‐adrenal (HPA) axis is critical for life. It has a circadian rhythm that anticipates the metabolic, immunoregulatory and cognitive needs of the active portion of the day, and retains an ability to react rapidly to perceived stressful stimuli. The circadian variation in glucocorticoids is very ‘noisy’ because it is made up from an underlying approximately hourly ultradian rhythm of glucocorticoid pulses, which increase in amplitude at the peak of circadian secretion. We have shown that these pulses emerge as a consequence of the feedforward–feedback relationship between the actions of corticotrophin hormone (ACTH) on the adrenal cortex and of endogenous glucocorticoids on pituitary corticotrophs. The adrenal gland itself has adapted to respond preferentially to a digital signal of ACTH and has its own feedforward–feedback system that effectively amplifies the pulsatile characteristics of the incoming signal. Glucocorticoid receptor signalling in the body is also adapted to respond in a tissue‐specific manner to oscillating signals of glucocorticoids, and gene transcriptional and behavioural responses depend on the pattern (i.e. constant or pulsatile) of glucocorticoid presentation. During major stressful activation of the HPA, there is a marked remodelling of the pituitary–adrenal interaction. The link between ACTH and glucocorticoid pulses is maintained, although there is a massive increase in the adrenal responsiveness to the ACTH signals.

Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis, neuropathology and glucocorticoid-based therapeutics

Glucocorticoids mediate plethora of actions throughout the human body. Within the brain, they modulate aspects of immune system and neuroinflammatory processes, interfere with cellular metabolism and viability, interact with systems of neurotransmission and regulate neural rhythms. The influence of glucocorticoids on memory and emotional behaviour is well known and there is increasing evidence for their involvement in many neuropsychiatric pathologies. These effects, which at times can be in opposing directions, depend not only on the concentration of glucocorticoids but also the duration of their presence, the temporal relationship between their fluctuations, the co-influence of other stimuli, and the overall state of brain activity. Moreover, they are region- and cell type-specific. The molecular basis of such diversity of effects lies on the orchestration of the spatiotemporal interplay between glucocorticoid- and mineralocorticoid receptors, and is achieved through complex dynamics, mainly mediated via the circadian and ultradian pattern of glucocorticoid secretion. More sophisticated methodologies are therefore required to better approach the study of these hormones and improve the effectiveness of glucocorticoid-based therapeutics.

The regulatory role of neurotensin on the hypothalamic-anterior pituitary axons: Emphasis on the control of thyroid-related functions

Neurotensin (NT) is a 13 amino acid neurohormone and/or neuromodulator, located in the synaptic vesicles and released from the neuronal terminals in a calcium-dependent manner. This peptide is present among mammalian and nonmammalian species, mainly in the central nervous system and the gastrointestinal tract. Due to its neuroendocrine activity, NT has been related to the pathophysiology of a series of disorders, such as schizophrenia, drug-abuse, Parkinsons disease, cancer, stroke, eating disorders and other neurodegenerative conditions. Moreover, NT participates in the physiology of pain-induction, central blood pressure control and inflammation. NT also plays an important interactive role in all components of the hypothalamic-anterior pituitary circuit, which is mediated by an endocrine, paracrine or/and autocrine manner, towards most of the anatomical regions that define this circuit. A considerable amount of data implicates NT in thyroid-related regulation through this circuit, the exact mechanisms of which should be further investigated for the potential development of more targeted approaches towards the treatment of thyroid-related endocrine diseases. The aim of this study was to provide an up-to-date review of the literature concerning the regulatory role of NT on the hypothalamic-anterior pituitary axons, with an emphasis on the control of thyroid-related functions.

Experimentally-induced maternal hypothyroidism alters crucial enzyme activities in the frontal cortex and hippocampus of the offspring rat.

Thyroid hormone insufficiency during neurodevelopment can result into significant structural and functional changes within the developing central nervous system (CNS), and is associated with the establishment of serious cognitive impairment and neuropsychiatric symptomatology. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism as a multilevel experimental approach to the study of hypothyroidism-induced changes on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a brain region-specific manner. This experimental approach has been recently developed and characterized by the authors based on neurochemical analyses performed on newborn and 21-day-old rat offspring whole brain homogenates; as a continuum to this effort, the current study focused on two CNS regions of major significance for cognitive development: the frontal cortex and the hippocampus. Maternal exposure to PTU in the drinking water during gestation and/or lactation resulted into changes in the activities of acetylcholinesterase and two important adenosinetriphosphatases (Na+,K+- and Mg2+-ATPase), that seemed to take place in a CNS-region-specific manner and that were dependent upon the PTU-exposure timeframe followed. As these findings are analyzed and compared to the available literature, they: (i) highlight the variability involved in the changes of the aforementioned enzymatic parameters in the studied CNS regions (attributed to both the different neuroanatomical composition and the thyroid-hormone-dependent neurodevelopmental growth/differentiation patterns of the latter), (ii) reveal important information with regards to the neurochemical mechanisms that could be involved in the way clinical hypothyroidism could affect optimal neurodevelopment and, ultimately, cognitive function, as well as (iii) underline the need for the adoption of more consistent approaches towards the experimental simulation of congenital and early-age-occurring hypothyroidism.

The importance of biological oscillators for HPA activity and tissue glucocorticoid response: Coordinating stress and neurobehavioural adaptation

The hypothalamic‐pituitary‐adrenal (HPA) axis is critical for life. It has a circadian rhythm that anticipates the metabolic, immunoregulatory and cognitive needs of the active portion of the day, and retains an ability to react rapidly to perceived stressful stimuli. The circadian variation in glucocorticoids is very ‘noisy’ because it is made up from an underlying approximately hourly ultradian rhythm of glucocorticoid pulses, which increase in amplitude at the peak of circadian secretion. We have shown that these pulses emerge as a consequence of the feedforward–feedback relationship between the actions of corticotrophin hormone (ACTH) on the adrenal cortex and of endogenous glucocorticoids on pituitary corticotrophs. The adrenal gland itself has adapted to respond preferentially to a digital signal of ACTH and has its own feedforward–feedback system that effectively amplifies the pulsatile characteristics of the incoming signal. Glucocorticoid receptor signalling in the body is also adapted to respond in a tissue‐specific manner to oscillating signals of glucocorticoids, and gene transcriptional and behavioural responses depend on the pattern (i.e. constant or pulsatile) of glucocorticoid presentation. During major stressful activation of the HPA, there is a marked remodelling of the pituitary–adrenal interaction. The link between ACTH and glucocorticoid pulses is maintained, although there is a massive increase in the adrenal responsiveness to the ACTH signals.

Intracerebroventricular administration of streptozotocin as an experimental approach to Alzheimer's disease

The in vivo experimental simulation of Alzheimers disease (AD) has been a field of paramount importance for Experimental Medicine and Neuroscience for more than 20 years. We herein provide a short overview of an experimental approach to sporadic AD that is based on the insulin-resistant state induced in the brains of animals following the intracerebroventricular (icv) administration of streptozotocin (STZ) at low doses. The icv administration of STZ is considered as an established, standardized and reproducible approach to sporadic AD, central aspects of the pathology of which it can reliably simulate.

Inhibition of Na+,K+-ATPase in the hypothalamus, pons and cerebellum of the offspring rat due to experimentally-induced maternal hypothyroidism

Abstract Neurodevelopment is known to be particularly susceptible to thyroid hormone insufficiency and can result in extensive structural and functional deficits within the central nervous system (CNS), subsequently leading to the establishment of cognitive impairment and neuropsychiatric symptomatology. The current study evaluated the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism (as a suggestive multilevel experimental approach to the study of hypothyroidism-induced changes that has been developed and characterized by the authors) on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a CNS region-specific manner. The activities of acetylcholinesterase (AChE), Na+,K+-ATPase and Mg2+-ATPase in the offspring hypothalamus, cerebellum and pons were assessed. The study demonstrated that maternal exposure to PTU (0.05% w/v in the drinking water) during the critical periods of neurodevelopment can result in an inhibition of hypothalamic, pontine and cerebellar Na+,K+-ATPase; a major marker of neuronal excitability and metabolic energy production as well as an important regulator of important systems of neurotransmission. On the other hand, no significant changes in the activities of the herein offspring CNS regions’ AChE and Mg2+-ATPase were recorded. The observed Na+,K+-ATPase inhibition: (i) is region-specific (and non-detectable in whole brain homogenetes), (ii) could constitute a central event in the pathophysiology of clinically-relevant hypothyroidism-associated developmental neurotoxicity, (iii) occurs under all examined experimental schemes, and (iv) certainly deserves further clarification at a molecular and histopathological level. As these findings are analyzed and compared to the available literature, they also underline the need for the adoption and further study of Na+,K+-ATPase activity as a consistent neurochemical marker within the context of a systematic comparative study of existing (and novel) simulation approaches to congenital and early age hypothyroidism.

Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man

Significance The hypothalamic-pituitary-adrenal axis is a critical neurohormonal network regulating homeostasis and coordinating stress responses. Here we demonstrate that an oscillating pattern of plasma cortisol is important for maintenance of healthy brain responses as measured by functional neuroimaging and behavioral testing. Our data highlight the crucial role of glucocorticoid rhythmicity in (i) modulating sleep behavior and working memory performance, and (ii) regulating the human brain’s responses under emotional stimulation. Current optimal cortisol replacement therapies for patients with primary or secondary adrenal insufficiently are associated with poor psychological status, and these results suggest that closer attention to aspects of chronotherapy will benefit these patients and may also have major implications for improved glucocorticoid dynamics in stress and psychiatric disease. Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy.