Estrogen Actions in the Central Nervous System 1

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The orbitofrontal cortex (OFC) has been implicated in the representation of emotional stimuli, assignment of emotional valence͞ salience to stimuli, stimulus-reinforcement association learning, motivation, and socio-emotional control. Using functional magnetic resonance imaging in female subjects without premenstrual mood symptoms, we found that OFC activity to emotional linguistic stimuli varies depending on the menstrual cycle phase. Specifically, anterior-medial OFC activity for negative vs. neutral stimuli was increased premenstrually and decreased postmenstrually. The inverse pattern was seen in the lateral OFC. These findings suggest that specific subregional OFC activity to emotional stimuli is modulated across the menstrual cycle. The data also demonstrate that menstrual cycle phase is an important consideration in further studies attempting to elucidate the neural substrates of affective representation.functional MRI ͉ brain ͉ mood ͉ emotion ͉ women D espite a vast literature describing sex hormone influences on the central nervous system and a growing emotional neuroscience literature, there are few data concerning the effects of menstrual cycle phase on the neurobiology of emotional processing in humans. This neuroimaging study specifically probes emotion and limbic activity across the menstrual cycle in women carefully characterized as having no premenstrual mood symptoms. Our results implicate the orbitofrontal cortex (OFC) as a key limbic region in which activity in response to emotional stimuli and behavioral demands is influenced by menstrual cycle phase.Damage to the OFC has long been associated with socioemotional dyscontrol (1-4). Patients with OFC lesions are prone to disadvantageous decision-making, perhaps because of an inability to evoke appropriate somatic-feeling states that would inform advantageous response selection. The OFC has been implicated in inhibitory control and emotional regulation, and has been hypothesized to have a specific role in emotion-influenced decision making (5-7).There is abundant evidence for OFC involvement in motivational operations (8). Rapid stimulus-reinforcement association learning is implemented in the OFC (8), and the OFC is important for the alteration of stimulus-reward associations (9). The OFC appears to respond to the pleasantness of some stimuli (10, 11) as well as to the unpleasantness of other stimuli (8,(12)(13)(14)(15).Regarding emotional processing, a metaanalysis of functional neuroimaging studies on OFC function supports a medio-lateral gradient for representation of positive and negative stimuli, respectively, and an anterio-posterior gradient for complex (higher-order͞ polymodal) and simple (lower-order͞unimodal) stimuli, respectively (16). However, some studies have found medial OFC activity to negative stimuli or lateral OFC activity to positive stimuli (17)(18)(19). Key issues in understanding these discrepancies include sensory modalities of presented stimuli, stimulus characteristics that may confound valence differences, and individu...

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle

Protopopescu

Pan²,

Altemus³

et al. 2005

189

128

“…B ehavioral, biochemical, and physiological data in animals demonstrate that the gonadal steroid hormones estrogen and progesterone affect behavior and modulate neuronal activity (1)(2)(3)(4). These hormones not only influence ovulation and reproductive behavior but also affect cognitive functions, affective state, vulnerability to drugs of abuse, and pain sensitivity.…”

mentioning

confidence: 99%

Menstrual cycle phase modulates reward-related neural function in women

Dreher

Schmidt

Kohn

et al. 2007

488

365

There is considerable evidence from animal studies that the mesolimbic and mesocortical dopamine systems are sensitive to circulating gonadal steroid hormones. Less is known about the influence of estrogen and progesterone on the human reward system. To investigate this directly, we used functional MRI and an event-related monetary reward paradigm to study women with a repeated-measures, counterbalanced design across the menstrual cycle. Here we show that during the midfollicular phase (days 4 -8 after onset of menses) women anticipating uncertain rewards activated the orbitofrontal cortex and amygdala more than during the luteal phase (6 -10 days after luteinizing hormone surge). At the time of reward delivery, women in the follicular phase activated the midbrain, striatum, and left fronto-polar cortex more than during the luteal phase. These data demonstrate augmented reactivity of the reward system in women during the midfollicular phase when estrogen is unopposed by progesterone. Moreover, investigation of between-sex differences revealed that men activated ventral putamen more than women during anticipation of uncertain rewards, whereas women more strongly activated the anterior medial prefrontal cortex at the time of reward delivery. Correlation between brain activity and gonadal steroid levels also revealed that the amygdalo-hippocampal complex was positively correlated with estradiol level, regardless of menstrual cycle phase. Together, our findings provide evidence of neurofunctional modulation of the reward system by gonadal steroid hormones in humans and establish a neurobiological foundation for understanding their impact on vulnerability to drug abuse, neuropsychiatric diseases with differential expression across males and females, and hormonally mediated mood disorders. B ehavioral, biochemical, and physiological data in animals demonstrate that the gonadal steroid hormones estrogen and progesterone affect behavior and modulate neuronal activity (1-4). These hormones not only influence ovulation and reproductive behavior but also affect cognitive functions, affective state, vulnerability to drugs of abuse, and pain sensitivity. Although ovarian steroids have widespread neurophysiological effects, including on the dopaminergic system, and although estrogen and progesterone receptors are densely present along midbrain dopaminergic neurons and other components of the reward system (such as the amygdala and striatum), little is known about the influences of estrogen and progesterone on the dopamine-dependent reward system in women.Substantial preclinical data, including behavioral and neurochemical differences between sexes, across the estrous cycle, and in postovariectomy hormone replacement (5, 6), attest to neuroregulatory effects of both estrogen and progesterone on the dopaminergic system (7, 8), not only on the tuberoinfundibular dopaminergic system involved in control of the anterior pituitary and important for ovulation and reproductive behavior, but also on the mesolimbic and mesocortical dopa...

“…ER␤ Ϫ/Ϫ mice have provided evidence for a role of ER␤ in emotional behavior, including depression, anxiety, and aggression (16)(17)(18). Although the exact mode of action by which ER␤ exerts its effects in the brain is not clear, it is very likely that the inhibitory neurotransmitter ␥-aminobutyric acid (GABA) is involved (19)(20)(21). Disruption of GABAergic interneuron development during the embryonic and early postnatal periods can have profound neurological and behavioral consequences, including an increased susceptibility to seizures, heightened anxiety, and diminished social interaction (22)(23)(24).…”

mentioning

confidence: 99%

Estrogen receptor β expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons

Fan

Warner

Gustafsson

2006

Our previous studies with estrogen receptor ␤ knockout (ER␤ ؊/؊ ) mice demonstrated that ER␤ is necessary for embryonic development of the brain as early as embryonic day 14.5 (E14.5) and is involved in neuronal migration. Such early effects of ER were unexpected because estradiol synthesis and action in the brain occur at E18.5. In the present study, we examined the distribution of ER␤ in the developing brain and identified a population of ER␤-regulated interneurons. ER␤ appears in the brain at E12.5, mainly localized in the wall of the midbrain, neuromere, hypothalamus, thalamus, and basal plate of pons. At E15.5 and E16.5, ER␤ expression increased in the hypothalamus, thalamus, and midbrain and appeared in the limbic forebrain. At E18.5, ER␤ expression was strongly expressed throughout the brain, including the cerebellum and striatum, whereas there were very few positive cells in the ventricular region. In the paraventricular thalamic nucleus and parafascicular nucleus, most of the calretinin-immunopositive interneurons expressed ER␤. In ER␤ ؊/؊ mice, calretinin expression was markedly lower than in WT mice in the hippocampus, thalamus, and amygdala both at E16.5 and at E18.5. Epidermal growth factor receptor expression was lower in the cortex of ER␤ ؊/؊ than in WT mice at E15.5 and, unlike WT mice, was absent from the superficial marginal zone. These findings suggest that ER␤ in the embryonic brain is necessary for the development of calretininimmunoreactive GABAergic interneurons and for neuronal migration in the cortex through modulating epidermal growth factor receptor expression at middle and later embryonic stages.cortex ͉ EGF receptor ͉ striatum ͉ thalamus E strogen is important during brain development, influencing the maturation of neural systems and affecting the sexual differentiation of brain structures and functions (1, 2). Sexual differentiation in the brain occurs in male rodents at day 18.5 when aromatase is induced in the brain and catalyses the synthesis of estradiol from testosterone secreted from the embryonic testis. At this time, estrogen imprints the neuroendocrine control of gonadal function, reproductive behavior, and the sexual differences in the secretion of growth hormone.Estrogen actions now are recognized to occur via two distinct estrogen receptors (ER), ER␣ and ER␤, that reside in cell nuclei (3, 4). In the brain, ER␣ plays a critical role in regulating reproductive neuroendocrine function, whereas ER␤ may be more important in regulating nonreproductive functions (5-8).In ER␣ knockout mice, no gross brain abnormalities have been reported, whereas ER␤ plays a prominent role during embryogenesis and there are significant morphological abnormalities in the embryonic brains of ER␤ knockout (ER␤ Ϫ/Ϫ ) mice (9). Studies have revealed that ER␤ also is expressed in fetal human brain and may mediate effects of estrogen in the developing nervous system (10). Lemmen et al. (11) reported that ER␤ mRNA is detectable in brains of mouse embryo at embryonic day 10.5 (E10.5), but there is no i...