Therapeutic implications of HPA axis abnormalities in Alzheimer's disease: review and update

The adaptive and maladaptive roles of the hypothalamic-pituitary-adrenal (HPA) axis in stressful conditions and in disorders such as major depression, posttraumatic stress disorder, and Cushing's syndrome, have been the subject of substantial, ongoing study. In particular, HPA disturbances have been associated with memory impairments, and hypercortisolemic conditions with atrophy of the hippocampus, a limbic structure closely associated with declarative memory. Recent discoveries support a more complicated picture of HPA axis function and pathology in acquiring, retrieving, and consolidating new memories. These findings include: the existence of an 'inverted U-shaped relationship" between stimulation of brain glucocorticoid receptors and memory performance; that distinct areas of the hippocampus have been found to respond differently to cortisol stimulation; and that hippocampal atrophy has been found to be potentially reversible in some conditions, although whether such atrophy is a cause or effect of these pathological conditions is currently unclear. More longitudinal studies of HPA axis function in aging normal individuals, those with mild cognitive impairment,and individuals with Alzheimer' disease, examining pertinent variables such as APOEe-4 status, are needed to help clarify these new findings. Antiglucocorticoid agents appear to have therapeutic value in particular conditions. These results are relevant for understanding and treating memory dysfunction in individuals with Alzheimer's disease, a disorder prominently and invariably characterized by early hippocampal lesions and memory impairment. Given the burden of this disease, we feel it timely to encourage controlled trials of antiglucocorticoid agents in the treatment of mild cognitive impairment and Alzheimers disease.     

Glucocorticoids and cognitive function: from physiology to pathophysiology

This paper reviews the literature on the relationship between glucocorticoids and cognitive functioning, including memory and selective attention. The main body of evidence suggests that hypothalamic-pituitary-adrenal (HPA) axis dysfunction or a state of hypercortisolaemia can be correlated with cognitive deficits specific to the medial temporal lobe declarative memory system. These impairments are discussed in relation to patients with HPA abnormalities, as seen in a significant number of patients with major depression or Cushing's syndrome, and also in relation to healthy volunteers after administration of glucocorticoids. It remains to be seen whether there are differential effects on acquisition, consolidation or retrieval processes. However, it would seem that glucocorticoids have a preferential effect on recall of information as opposed to recognition, possibly because recognition is more automatic.Type 2 glucocorticoid receptors (GRs), which are occupied by cortisol in humans in times of stress, are thought to be responsible for the glucocorticoid-induced memory impairment. GRs alter the feedback of the HPA axis, which in turn disrupts hippocampal functioning. While this can be reversible, animal studies suggest that chronic elevation of glucocorticoid levels can lead to the loss of hippocampal neurons and irreversible decline in declarative memory. Copyright 2001 John Wiley & Sons, Ltd.     

The role of hippocampus in the pathophysiology of bipolar disorder

Bipolar disorder (BD) is thought to be associated with abnormalities within discrete brain regions associated with emotional regulation, particularly in fronto-limbic-subcortical circuits. Several reviews have addressed the involvement of the prefrontal cortex in the pathophysiology of BD, whereas little attention has been given to the role of the hippocampus. This study critically reviews data from brain imaging, postmortem, neuropsychological, and preclinical studies, which suggested hippocampal abnormalities in BD. Most of the structural brain imaging studies did not find changes in hippocampal volume in BD, although a few studies suggested that anatomical changes might be restricted to the psychotic, pediatric, or unmedicated BD subgroups. Functional imaging studies showed abnormal brain activation in the hippocampus and its closely related regions during emotional, attentional, and memory tasks. This is consistent with neuropsychological findings that revealed a wide range of cognitive disturbances during acute mood episodes and a significant impairment in declarative memory during remission. Postmortem studies indicate abnormal glutamate and GABA transmission in the hippocampus of BD patients, whereas data from preclinical studies suggest that the regulation of hippocampal plasticity and survival might be associated with the therapeutic effects of mood stabilizers. In conclusion, the available evidence suggests that the hippocampus plays an important role in the pathophysiology of BD.     

Formation mechanisms of stress adaptation: role of functional coupling of glucocorticoids and brain serotonergic nervous system]

It is known that the incompetence of stress adaptation mechanisms is a primary factor affecting disorders such as anxiety and depression. Increased clinical evidence indicates that hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis and dysfunction of the brain serotonin (5-HT) nervous system are risk factors associated with these disorders. Given the high sensitivity of hippocampal 5-HT responses to glucocorticoids, functional changes in the hippocampal 5-HT nervous system induced by chronic hypercorticism are attracting more attention. Repeated exposure to stress stimuli or chronic administration of corticosterone produces hippocampal 5-HT1A receptor dysfunction as well as an imbalance in mineralocorticoid and glucocorticoid receptors. We recently demonstrated that activation of the 5-HT1A receptors facilitates the adaptive responses to stress stimuli by acting on the HPA axis. These findings suggest that abnormal coupling of glucocorticoid-mineralocorticoid/glucocorticoid receptors-5-HT1A receptors in the hippocampus may be one factor disrupting adaptation to stress situations. Moreover, it is shown that activation of the coupling system affects learning and memory processes associated with stress stimuli. These findings suggest that the functional coupling of glucocorticoid-mineralocorticoid/glucocorticoid receptors and serotonergic neurons in the brain may play a significant role in the recognition of stress stimuli and induction of stress adaptation, and dysfunction of this coupling system may be related to the onset of affective disorders.     

Functional interaction between 5-HT(6) receptors and hypothalamic-pituitary-adrenal axis: cognitive implications

The serotonin 5-HT(6) receptor has become a promising target for the treatment of neuropsychological diseases, such as affective disorders. Increasing evidence implicates stress and its effector system, the hypothalamic-pituitary-adrenal (HPA) axis, in the neurobiology of depression. In addition, there are important memory disturbances in stress-related psychiatric disorders that have been associated to an impairment of the HPA axis reactivity. The aim of the present work is to study the functional interactions between 5-HT(6) receptors and HPA axis. In a situation of increased HPA axis responsiveness (maternal separation, MS) no differences were found in the expression of 5-HT(6) gene in the hippocampus or frontal cortex, although serotonin levels were higher in the frontal cortex of MS rats. 5-HT(6) receptor mRNA expression increased significantly in the hippocampus in a situation of decreased glucocorticoid levels, such as adrenalectomy. Cognitive deficits associated to HPA dysfunction, such those found in the MS model, were fully reversed by administration of SB271046, a selective 5-HT(6) receptor antagonist. A chronic treatment with SB271046 did not modify CRF mRNA levels in the hypothalamus, but there was a higher glucocorticoid receptor density in the hippocampus compared to control. In contrast, in the frontal cortex, treatment with SB271046 induced a significant decrease in glucocorticoid receptor density. These data suggest that expression of 5-HT(6) receptors might be differentially regulated depending on levels of circulating adrenal corticoids. These results are discussed in terms of therapeutical approaches to the treatment of behavioral (depressive-like) and cognitive disturbances associated to an altered response to stress.     

Antiglucocorticoid drugs in the treatment of depression

A confluence of evidence indicates that prolonged elevation in gluco-corticoid level may result in disturbances of mood and cognition. In Cushing’s syndrome, hypersecretion of cortisol is associated with a high incidence of depression, impairment in memory and hippocampal atrophy. Pharmacological usage of glucocorticoids is similarly productive of mood change and memory deficit. In patients with endogenous depression, hypercortisolaemia is associated with cognitive dysfunction and possibly a decrease in hippocampal volume. In each of these conditions, reduction of glucocorticoid level, either through discontinuation of steroid treatment or through usage of agents that block glucocorticoid synthesis, ameliorates the adverse behavioural effects. Traditional antidepressant agents may, in addition, stabilise mood through actions on the hypothalamic-pituitary adrenocortical (HPA) system. Although clinical usage of the currently available antigluco-corticoid drugs is limited by significant adverse side effect profiles, development of drugs specifically targeting the glucocorticoid receptor may lead to innovative strategies in the treatment of mood disorders.     

Selective effects of acute serotonin and catecholamine depletion on memory in healthy women

There is converging evidence that brain serotonin and dopamine may selectively modulate learning and memory in humans. However, this has not been directly demonstrated. In the current study, we used the method of amino acid precursor depletion to explore the effects of low serotonin and catecholamine function on memory in healthy female volunteers. Participants completed three experimental sessions: (i) tryptophan depletion (TD to lower 5-HT); (ii) tyrosine and phenylalanine depletion (TPD to lower catecholamines); and (iii) a balanced control condition (Bal). All testing was conducted in a double-blind, placebo-controlled, crossover design. Cognitive and mood assessments were performed at baseline and 5 h after ingesting the amino acid mixture. Consistent with previous studies, TD impaired declarative memory consolidation on a structured word-learning task, while TPD, acting to lower brain dopamine availability, impaired spatial working memory. No secondary deficits were observed on measures of attention, short-term memory or subjective mood state. These findings suggest that low brain serotonin versus dopamine selectively impairs memory performance in humans. This may shed light on the role of these neurotransmitters in disorders that are characterized by significant memory impairment.     

Hippocampal Network Connectivity and Activation Differentiates Post-Traumatic Stress Disorder From Generalized Anxiety Disorder

Anxiety disorders are a diverse group of clinical states. Post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), eg, share elevated anxiety symptoms, but differ with respect to fear-related memory dysregulation. As the hippocampus is implicated in both general anxiety and fear memory, it may be an important brain locus for mapping the similarities and differences among anxiety disorders. Anxiety and fear also functionally associate with different subdivisions of the hippocampus along its longitudinal axis: the human posterior (rodent dorsal) hippocampus is involved in memory, through connectivity with the medial prefrontal-medial parietal default-mode network, whereas the anterior (rodent ventral) hippocampus is involved in anxiety, through connectivity with limbic-prefrontal circuits. We examined whether differential hippocampal network functioning may help account for similarities and differences in symptoms in PTSD and GAD. Network-sensitive functional magnetic resonance imaging-based resting-state intrinsic connectivity methods, along with task-based assessment of posterior hippocampal/default-mode network function, were used. As predicted, in healthy subjects resting-state connectivity dissociated between posterior hippocampal connectivity with the default-mode network, and anterior hippocampal connectivity to limbic-prefrontal circuitry. The posterior hippocampus and the associated default-mode network, across both resting-state connectivity and task-based measures, were perturbed in PTSD relative to each of the other groups. By contrast, we found only modest support for similarly blunted anterior hippocampal connectivity across both patient groups. These findings provide new insights into the neural circuit-level dysfunctions that account for similar vs different features of two major anxiety disorders, through a translational framework built on animal work and carefully selected clinical disorders.     

Allopregnanolone regulates neurogenesis and depressive/anxiety-like behaviour in a social isolation rodent model of chronic stress

Chronic stress has been implicated as a causal factor in depression and anxiety, and is associated with neuroendocrine dysfunction and impaired hippocampal neurogenesis. The neurosteroid allopregnanolone (3α,5α-THP; ALLO) has been shown to be reduced in depressed patients. ALLO is “stress responsive” and plays a major role in regulating hypothalamic-pituitary-adrenal (HPA) axis function. We propose that reduced ALLO levels following chronic stress leads to HPA hyperactivity due to diminished ALLO regulation. This will result in increased glucocorticoid levels and reduced BDNF expression, leading to impaired hippocampal neurogenesis and the precipitation of depression/anxiety. To investigate this, chronic stress was induced using the social isolation model and depressive/anxiety-like behaviour assessed using the novelty-suppressed feeding test and forced-swim test. The social isolation model was associated with a significant reduction in endogenous ALLO levels and a depressive/anxiety-like behavioural profile. When exogenous ALLO was administered from the onset of isolation it prevented the development of depressive/anxiety-like behaviours and impairment of hippocampal neurogenesis. When treatment was initiated following six weeks of social isolation, behavioural profile was restored and deficits in BDNF and neurogenesis were not observed. Supporting our hypothesis we observed that socially isolated animals exhibited reduced HPA responsiveness, which was either prevented or normalised with ALLO treatment. Combined, these results indicate that administration of exogenous ALLO either during or following a period of chronic stress can prevent or normalise HPA dysfunction and impairment of hippocampal neurogenesis respectively, precluding the establishment of depressive/anxiety-like behaviours. ALLO may therefore provide a novel therapeutic target for the treatment of depression/anxiety.     

Differential environmental regulation of neurogenesis along the septo-temporal axis of the hippocampus

The hippocampus is involved in both cognitive and emotional processing; these different functions are topographically distributed along its septo-temporal axis, the dorsal (septal) hippocampus being preferentially involved in cognitive processes such as learning and memory while the ventral (temporal) hippocampus participates in emotional regulation and anxiety-related behaviors. Newborn hippocampal neurons become functionally integrated into hippocampal networks and are likely to contribute to hippocampal functions, but whether their regulation and function are homogenous throughout this axis is not clear. Here we investigate changes in cell proliferation and neurogenesis along the septo-temporal axis of the hippocampus induced by the Unpredictable Chronic Mild Stress model of depression (UCMS), chronic fluoxetine treatment and enriched environment. Mice were either subjected to UCMS, standard housing or enriched environment. Stress-exposed mice were treated daily with fluoxetine (10 mg/kg) or vehicle. Effects of UCMS regimen, fluoxetine treatment and enrichment were assessed by physical measures and behavioral testing. Quantitative changes in cell proliferation and neurogenesis were assessed by immunohistochemistry using BrdU labeling. Results indicate that UCMS decreased cell proliferation and neurogenesis preferentially in the ventral hippocampus, an effect that was reversed by fluoxetine treatment. Environmental enrichment on the other hand increased cell proliferation in both divisions but promoted neurogenesis only in the dorsal hippocampus. These results indicate that environmental factors can differentially regulate neurogenesis in a region-specific manner. This may possibly underlie heterogeneous function of newborn neurons along the septo-temporal axis of the hippocampus and have functional significance as to their implication in stress related disorders and memory processes.     

New therapeutic strategy for mood disorders

The development of new treatments for mood disorders, as anxiety and depression, is based on identification of neural substrates and the mechanisms underlying their etiology and pathophysiology. The heterogeneity of mood disorders indicates that its origin may lie in dysfunction of multiple brain regions (amygdala, nucleus accumbens, hippocampus, prefrontal cortex and cingulate cortex). The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests the contribute of new neurons to the biology of mood disorders that is still under debate. The production of new neurons, referred to as neurogenesis, occurs throughout life in discrete brain areas such as the dentate gyrus (DG) of the hippocampus and the subventricular zone/olfactory bulb. Findings describing that neurogenesis process in DG is increased by antidepressants, like fluoxetine, and it is required for the behavioral effect of antidepressants, lead to a new strategy and drugs for the treatment of mood disorders. As many patients display poor response to therapy, research on depression and antidepressant drugs is necessary. In this regard, focusing on neurogenesis and neuroplasticity processes in experimental models is particularly interesting for the understanding of the pathophysiology of mood disorders and should define the role of adult-born neurons in hippocampal physiology. Different classes of drugs are currently prescribed for the treatment of mood disorders. Among them selective serotonin reuptake (SSRIs), monoamine oxidase inhibitors (MAOIs), specific norepinephrine reuptake inhibitors (SNRIs) and tricyclic acids (TCA) alleviate symptoms of mood disorders. Here we review different strategies that may be adopted for impairing mood disorders and that may be further developed for innovative therapeutic approaches.     

Insulin signaling effects on memory and mood

The escalating obesity/diabetes epidemic is an important health-care issue that has crucial socio-economic ramifications. The complications of diabetes/obesity phenotypes extend to the central nervous system (CNS), including the hippocampus, a brain region that is particularly vulnerable to hyperglycemia and insulin resistance. Deficits in hippocampal synaptic plasticity observed in diabetes ultimately have deleterious consequences upon cognitive function. For example, recent studies using brain imaging technologies have identified cerebral atrophy in diabetic patients, suggesting that the neuroanatomical changes observed in experimental models of diabetes may accurately reflect what is occurring in the clinical setting. Deficits in insulin receptor (IR) signaling and impairments in hypothalamic-pituitary-adrenal (HPA) axis function also contribute to the neurological complications of diabetes phenotypes. The pathophysiological similarities between diabetes and stress-related mood disorders suggest that common mechanistic mediators may be involved in the etiology and progression of the neurological complications of these disorders. When combined with the accumulating evidence from pre-clinical models, these data support the hypothesis that a long-term consequence of diabetes/obesity phenotypes is accelerated brain aging that results in neuropsychological deficits and increased vulnerability to co-morbidities such as depressive illness.     

The role of corticotropin-releasing hormone in the pathophysiology of depression: therapeutic implications

Stress responses have been posited to be a key component of mental health and disease by playing essential roles both in normal adaptive processes and maladaptive physiological responses that in part underlie the pathogenesis of certain subtypes of mood and anxiety disorders. Early research focused on delineating the function of the hypothalamic-pituitary-adrenal (HPA) axis and subsequently examined its role in mediating the mammalian stress responses and its hyperactivity in depression. Much evidence now supports an important function of the biological mediators of this system in relation to not only depression, but also anxiety, substance abuse, and psychotic disorders, and implicates several components of this system as areas of intervention for novel pharmacotherapy. Perhaps the best studied central nervous system (CNS) component of this system is corticotropin-releasing factor (CRF), and considerable research has focused on its role in the HPA axis, as well in extrahypothalamic brain regions.     

Treatment Strategies Targeting Excess Hippocampal Activity Benefit Aged Rats with Cognitive Impairment

Excess neural activity in the CA3 region of the hippocampus has been linked to memory impairment in aged rats. We tested whether interventions aimed at reducing this excess activity would improve memory performance. Aged (24 to 28 months old) male Long–Evans rats were characterized in a spatial memory task known to depend on the functional integrity of the hippocampus, such that aged rats with identified memory impairment were used in a series of experiments. Overexpression of the inhibitory neuropeptide Y 13–36 in the CA3 via adeno-associated viral transduction was found to improve hippocampal-dependent long-term memory in aged rats, which had been characterized with impairment. Subsequent experiments with two commonly used antiepileptic agents, sodium valproate and levetiracetam, similarly produced dose-dependent memory improvement in such aged rats. Improved spatial memory with low doses of these agents was observed in both appetitve and aversive spatial tasks. The benefits of these different modalities of treatment are consistent with the concept that excess activity in the CA3 region of the hippocampus is a dysfunctional condition that may have a key role underlying age-related impairment in hippocampal-dependent memory processes. Because increased hippocampal activation occurs in age-related memory impairment in humans as observed in functional neuroimaging, the current findings also suggest that low doses of certain antiepileptic drugs in cognitively impaired elderly humans may have therapeutic potential and point to novel targets for this indication.     

Hippocampal to pituitary volume ratio: a specific measure of reciprocal neuroendocrine alterations in alcohol dependence.

OBJECTIVE: Studies to date provide conflicting views of the relationship between corticosteroids and decreased hippocampal volume in alcoholism. If this were mediated through the hypothalamic-pituitary-adrenal (HPA) axis, enlarged pituitary volumes relative to hippocampal volumes might be expected and be measurable using the hippocampus to pituitary volume (H:P) ratio. METHOD: Using magnetic resonance imaging (MRI), we performed volumetric analysis of the pituitary and hippocampus on 10 subjects with alcohol dependence (AD) and on 10 normal control subjects. RESULTS: Compared to normal controls, AD subjects demonstrated a trend towards decreased hippocampal volume (p < .06) and increased pituitary volume (p < .07). More importantly, H:P ratios were significantly smaller in AD subjects (p < .01). This observation persisted even when covaried for age. CONCLUSIONS: Reduced H:P ratio fits the hypothesis that ethanol stimulates pituitary corticotrophs resulting in elevated corticosteroid levels and possible injury to the hippocampus. If replicated, reduced H:P ratio may serve as a clinical measure of reciprocal neuroendocrine changes in chronic heavy ethanol use.     

Acute tryptophan depletion does not alter central or plasma brain-derived neurotrophic factor in the rat.

Dietary induced acute tryptophan depletion (ATD) is used to reduce central serotonergic function and to investigate the role of serotonin (5-HT) in psychiatric illness. In healthy volunteers ATD produces working memory deficits and decreases mood in some studies. Brain-derived neurotrophic factor (BDNF) plays a role in both cognition and in the regulation of mood; however, the possible contribution of central BDNF changes to the effects of ATD has not been examined. Therefore, using a rat model we have examined the effect of amino acid mixture-induced ATD on plasma and central BDNF protein levels. ATD significantly reduced free-plasma TRP by 79% and central hippocampal 5-HT by 35% when compared to controls. However, plasma or central BDNF protein levels in the hippocampus and midbrain were not significantly altered by ATD. These results suggest that changes in central BDNF do not contribute to the cognitive or mood effects of ATD.     

Disturbances of the stress response: the role of the HPA axis during alcohol withdrawal and abstinence

Interactions among the brain, the pituitary gland, and the adrenal glands (i.e., the hypothalamic-pituitary-adrenal [HPA] axis) help regulate the body's response to stress. The adrenal hormone cortisol plays a key role in stress reduction through its effects on multiple body systems. Excessive cortisol activity during both chronic alcohol administration and withdrawal may underlie some of the clinical complications of alcoholism, including increased risk of infectious diseases; bone, muscle, and reproductive system changes; altered energy metabolism; and disorders of mood and intellect. Despite excessive cortisol levels during intoxication and withdrawal, however, the HPA axis becomes less responsive to stress during abstinence, potentially resulting in an impaired capacity to cope with relapse-inducing stressors.