David M. Lyons

Neuroendocrine aspects of hypercortisolism in major depression

A consistent finding in biological psychiatry is that hypothalamic-pituitary-adrenal (HPA) axis physiology is altered in humans with major depression. These findings include hypersecretion of cortisol at baseline and on the dexamethasone suppression test. In this review, we present a process-oriented model for HPA axis regulation in major depression. Specifically, we suggest that acute depressions are characterized by hypersecretion of hypothalamic corticotropin-releasing factor, pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol. In chronic depressions, however, enhanced adrenal responsiveness to ACTH and glucocorticoid negative feedback work in complementary fashion so that cortisol levels remain elevated while ACTH levels are reduced. In considering the evidence for hypercortisolism in humans, studies of nonhuman primates are presented and their utility and limitations as comparative models of human depression are discussed.

Cocaine Self-Administration Produces a Progressive Involvement of Limbic, Association, and Sensorimotor Striatal Domains

The primate striatum is composed of limbic, cognitive, and sensorimotor functional domains. Although the effects of cocaine have generally been associated with the ventral striatum, or limbic domain, recent evidence in rodents suggests the involvement of the dorsal striatum (cognitive and sensorimotor domains) in cocaine self-administration. The goals of the present studies were to map the topography of the functional response to cocaine throughout the entire extent of the striatum of monkeys self-administering cocaine and determine whether this response is modified by chronic exposure to cocaine. Rhesus monkeys were trained to self-administer 0.3 mg/kg per injection cocaine for 5 d (initial stages; n = 4) or 100 d (chronic stages; n = 4) and compared with monkeys trained to respond under an identical schedule of food reinforcement (n = 6). Monkeys received 30 reinforcers per session, and metabolic mapping was conducted at the end of the 5th or 100th self-administration session. In the initial phases of cocaine exposure, self-administration significantly decreased functional activity in the ventral striatum, but only in very restricted portions of the dorsal striatum. With chronic cocaine self-administration, however, the effects of cocaine intensified and spread dorsally to include most aspects of both caudate and putamen. Early experiences with cocaine, then, involve mainly the limbic domain, an area that mediates motivational and affective functions. In contrast, as exposure to cocaine continues, the impact of cocaine impinges progressively on the processing of sensorimotor and cognitive information, as well as the affective and motivational information processed in the ventral striatum.

Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain.

Corticosteroids have been implicated in hippocampal atrophy in patients with severe psychiatric disorders, but little is known about receptor expression for corticosteroids in human or nonhuman primate brain. Both the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) were surveyed in this study of squirrel monkey brain using in situ hybridization histochemistry. Regions of high GR mRNA levels included CA1 and CA2 of hippocampus, dentate gyrus, paraventricular hypothalamus, lateral geniculate, lateral>medial amygdala, and cerebellum. Western analysis confirmed that GR immunoreactivity in squirrel monkey brain tissue most likely reflects the alpha isoform. Regions of high MR mRNA levels included all hippocampal pyramidal cell fields, dentate gyrus granule cell layer, lateral septum, medial>lateral amygdala, and to a lesser extent, cerebellum. Low levels of MR were also expressed in caudate and putamen. Receptor expression for corticosteroids in deep brain structures and the hippocampal formation was similar to that previously reported in rodents, but GR and MR mRNA were expressed at higher levels in squirrel monkey cerebral cortex. GR expression was evident in all cortical layers, particularly the pyramidal cell-rich layers II/III and V. MR expression was restricted to the more superficial cortical layers, and was only moderately represented in layer V. Laminar patterns were apparent in all regions of cortex for GR expression in squirrel monkeys, but low MR mRNA levels were found in dorsomedial prefrontal cortex (PFC). Different subregional distributions and distinctive laminar patterns suggest specialized functions or coordinated interactions between GR and MR mediated functions in primate PFC.

Individual differences in temperament of domestic dairy goats: constancy and change

Change is an essential property of development, yet some element of stability or consistency is necessary for the maintenance of individual distinctiveness. The issues of constancy and change were addressed in a study of individual differences in temperament of domestic dairy goats, Capra hircus. Within-individual stability was assessed on an absolute basis by evaluating changes in mean scores on five behavioural measures monitored in goat-human encounters at 14, 22 and 30 weeks of age. Between-individual stability was examined by comparing rank orders of individuals across successive ages and situations. Human-reared goats consistently expressed low levels of timidity. Behaviour of dam-reared goats increasingly resembled that of human-reared goats, while relative individual differences remained stable. Individual differences in timidity scores, derived from five interrelated behaviour measures, reliably predicted differences in pituitary-adrenal responsiveness at 14–30 weeks and behavioural outcomes in five different situations at 55 weeks. Timidity scores of all dam-reared goats exceeded scores of human-reared goats. Among seven pairs of fraternal twins, a goats rank within the dam-reared group predicted its siblings rank within the human-reared group. An individuals genotype and its early postnatal environment both contributed to processes underlying the development of stable individual differences in temperament of domestic dairy goats.

Intranasal oxytocin administration attenuates the ACTH stress response in monkeys

Social relationships protect against the development of stress-related psychiatric disorders, yet little is known about the neurobiology that regulates this phenomenon. Recent evidence suggests that oxytocin (OT), a neuropeptide involved in social bond formation, may play a role. This experiment investigated the effects of chronic intranasal OT administration on acute stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation in adult female squirrel monkeys. Subjects were randomized to one of two experimental conditions. Monkeys were intranasally administered either 50 microg oxytocin (N = 6 monkeys) or 0 microg oxytocin (N = 6 monkeys)/300 microl saline once a day for eight consecutive days. Immediately after drug administration on the eighth day, all monkeys were exposed to acute social isolation. Blood samples for determinations of adrenocorticotropic hormone (ACTH) and cortisol concentrations were collected after 30 and 90 min of stress exposure. Consistent with an anti-stress effect, OT-treated monkeys exhibited lower ACTH concentrations compared to saline-treated monkeys after 90 min of social isolation (F(1,7) = 6.891; P = 0.034). No drug-related differences in cortisol levels were observed, indicating that OT does not directly attenuate the adrenal stress response. Intranasal peptide administration has been shown to penetrate the central nervous system, and research must determine whether intranasally delivered OT exerts its effect(s) at a pituitary and/or brain level. This primate model offers critical opportunities to improve our understanding of the anti-stress effects of OT and may lead to novel pharmacological treatments for stress-related psychiatric disorders.

Salivary cortisol levels in socially phobic adolescent girls.

Anxiety disorders such as social phobia (SP) often have their onset during adolescence and frequently precede the onset of major depression. Dysregulation of the hypothalamic‐pituitary‐adrenal (HPA) axis is well‐documented in major depression. Consequently, there is considerable interest in HPA function in anxiety disorders. We examined salivary cortisol levels in 27 SP adolescent girls and 21 matched controls during normal daily activities, and immediately before and after a modified Trier Social Stress Test (TSST). Both SP subjects and controls showed significant elevations in cortisol levels prior to the TSST, and prior to attending school. These results suggest that salivary cortisol is a sensitive measure of anticipatory anxiety, but we failed to find significant differences between SP subjects and controls. Depression and Anxiety 10:25–27, 1999.

Animal models of early life stress: Implications for understanding resilience

In the mid-1950s, Levine and his colleagues reported that brief intermittent exposure to early life stress diminished indications of subsequent emotionality in rats. Here we review ongoing studies of a similar process in squirrel monkeys. Results from these animal models suggest that brief intermittent exposure to stress promotes the development of arousal regulation and resilience. Implications for programs designed to enhance resilience in human development are discussed.

Developmental Cascades Linking Stress Inoculation, Arousal Regulation, and Resilience

Stressful experiences that are challenging but not overwhelming appear to promote the development of arousal regulation and resilience. Variously described in studies of humans as inoculating, steeling, or toughening, the notion that coping with early life stress enhances arousal regulation and resilience is further supported by longitudinal studies of squirrel monkey development. Exposure to early life stress inoculation diminishes subsequent indications of anxiety, increases exploration of novel situations, and decreases stress-levels of cortisol compared to age-matched monkeys raised in undisturbed social groups. Stress inoculation also enhances prefrontal-dependent cognitive control of behavior and increases ventromedial prefrontal cortical volumes. Larger volumes do not reflect increased cortical thickness but instead represent surface area expansion of ventromedial prefrontal cortex. Expansion of ventromedial prefrontal cortex coincides with increased white matter myelination inferred from diffusion tensor magnetic resonance imaging. These findings suggest that early life stress inoculation triggers developmental cascades across multiple domains of adaptive functioning. Prefrontal myelination and cortical expansion induced by the process of coping with stress support broad and enduring trait-like transformations in cognitive, motivational, and emotional aspects of behavior. Implications for programs designed to promote resilience in humans are discussed.

Stress-Induced Changes in Corticosteroid Receptor Expression in Primate Hippocampus and Prefrontal Cortex

Neurobiological studies of stress often focus on the hippocampus where cortisol binds with different affinities to two types of corticosteroid receptors, i.e., mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The hippocampus is involved in learning and memory, and regulates the neuroendocrine stress response, but other brain regions also play a role, especially prefrontal cortex. Here, we examine MR and GR expression in adult squirrel monkey prefrontal cortex and hippocampus after exposure to social stress in infancy or adulthood. In situ hybridization histochemistry with (35)S-labeled squirrel monkey riboprobes and quantitative film autoradiography were used to measure the relative distributions of MR and GR mRNA. Distinct cortical cell layer-specific patterns of MR expression differed from GR expression in three prefrontal regions. The relative distributions of MR and GR also differed in hippocampal Cornu Ammonis (CA) regions. In monkeys exposed to adult social stress compared to the no-stress control, GR expression was diminished in hippocampal CA1 (P=0.021), whereas MR was diminished in cell layer III of ventrolateral prefrontal cortex (P=0.049). In contrast, exposure to early life stress diminished GR but not MR expression in cell layers I and II of dorsolateral prefrontal cortex (Ps<0.048). Similar reductions likewise occurred in ventrolateral prefrontal cortex, but the effects of early life stress on GR expression in this region were marginally not significant (P=0.053). These results provide new information on regional differences and the long-term effects of stress on MR and GR distributions in corticolimbic regions that control cognitive and neuroendocrine functions.

Stress-induced changes in primate prefrontal profiles of gene expression

Stressful experiences that consistently increase cortisol levels appear to alter the expression of hundreds of genes in prefrontal limbic brain regions. Here, we investigate this hypothesis in monkeys exposed to intermittent social stress-induced episodes of hypercortisolism or a no-stress control condition. Prefrontal profiles of gene expression compiled from Affymetrix microarray data for monkeys randomized to the no-stress condition were consistent with microarray results published for healthy humans. In monkeys exposed to intermittent social stress, more genes than expected by chance appeared to be differentially expressed in ventromedial prefrontal cortex compared to monkeys not exposed to adult social stress. Most of these stress responsive candidate genes were modestly downregulated, including ubiquitin conjugation enzymes and ligases involved in synaptic plasticity, cell cycle progression and nuclear receptor signaling. Social stress did not affect gene expression beyond that expected by chance in dorsolateral prefrontal cortex or prefrontal white matter. Thirty four of 48 comparisons chosen for verification by quantitative real-time polymerase chain reaction (qPCR) were consistent with the microarray-predicted result. Furthermore, qPCR and microarray data were highly correlated. These results provide new insights on the regulation of gene expression in a prefrontal corticolimbic region involved in the pathophysiology of stress and major depression. Comparisons between these data from monkeys and those for ventromedial prefrontal cortex in humans with a history of major depression may help to distinguish the molecular signature of stress from other confounding factors in human postmortem brain research.