The relationship between subjective difficulty in interoceptive processing and accuracy of heartbeat perception in autistic individuals.

Most autistic people experience difficulties in sensory processing, including interoceptive processing. For example, they often report subjective difficulties in the interoceptive processing of interoceptive input, such as difficulty in interpreting bodily signals, including hunger, thirst, and fatigue. However, whether these subjective interoceptive difficulties are from underlying problems in interoceptive accuracy remains unclear. This study investigated the relationship between subjective interoceptive difficulty and behavioral interoceptive accuracy in autistic adults and a control group. Subjective interoceptive accuracy was measured using an interoceptive sensitivity questionnaire, and behavioral interoceptive accuracy was measured using a heartbeat counting task. The results showed no significant relationship between subjective interoceptive difficulty and behavioral interoceptive accuracy in the autistic or control groups. This suggests that subjective interoceptive difficulty and behavioral interoceptive accuracy reflect different aspects of interoceptive processing. One possible interpretation is that autistic adults can identify individual local sensory inputs, such as heartbeats, however, they have difficulty integrating multiple inputs and recognizing internal body states such as hunger and fatigue.

Prior brief meditation reduces distractor inhibition during cognitive interference.

Background: Mindfulness meditation, comprising focused attention and open monitoring meditations, has been shown to enhance performance on cognitive interference tasks. While this enhancement has been considered not to result from distractor inhibition, no empirical evidence has been provided through behavioral data. In this study, we investigated whether 30-min interventions of focused attention and open monitoring meditations could reduce distractor inhibition in 72 meditation-naïve participants divided into focused attention meditation, open monitoring meditation, and control groups. Methods: We employed a task set that combined a cognitive interference task with subsequent preference judgment and surprise recognition tasks, utilizing the mere exposure effect paradigm, along with state and trait questionnaires. The mere exposure effect shows that repeated exposure to face images increases one's preference for them. However, this effect is reduced if participants consciously or unconsciously try to inhibit the face images during stimulus processing. In the cognitive interference task, they judged the direction of the letter superimposed on a distractor face image. In the subsequent preference judgment task, they were asked to rate the preference of face images, half of which were presented in the interference task and the remaining half were not presented. We hypothesized that inhibiting face images presented as distractors would lead to a decrease in preference for them. Results and discussions: We found that the mere exposure effect was observed in focused attention meditation and open monitoring meditation groups but not in the control group, indicating that compared to the control, focused attention and open monitoring meditations reduce inhibition processes for distractors during cognitive interference tasks. Furthermore, we found a positive correlation between the intensity of the mere exposure effect and state relaxation before the cognitive interference task as well as a negative correlation between the intensity of the mere exposure effect and state anxiety in the focused attention meditation group, but not in the open monitoring meditation group. This suggests that the processes of reducing inhibition in focused attention and open monitoring meditations differ. Our findings contribute to understanding the attentional mechanisms underlying mindfulness meditation during cognitive interference.

Estradiol rapidly rescues synaptic transmission from corticosterone-induced suppression via synaptic/extranuclear steroid receptors in the hippocampus.

We investigated rapid protection effect by estradiol on corticosterone (CORT)-induced suppression of synaptic transmission. Rapid suppression by 1 µM CORT of long-term potentiation (LTP) at CA3-CA1 synapses was abolished via coperfusion of 1 nM estradiol. N-methyl-D-aspartate (NMDA) receptor-derived field excitatory postsynaptic potential (NMDA-R-fEPSP) was used to analyze the mechanisms of these events. Estradiol abolished CORT-induced suppression of NMDA-R-fEPSP slope. This CORT-induced suppression was abolished by calcineurin inhibitor, and the rescue effect by estradiol on the CORT-induced suppression was inhibited by mitogen-activated protein (MAP) kinase inhibitor. The CORT-induced suppressions of LTP and NMDA-R-fEPSP slope were abolished by glucocorticoid receptor (GR) antagonist, and the restorative effects by estradiol on these processes were mimicked by estrogen receptor α (ERα) and ERß agonists. Taken together, estradiol rapidly rescued LTP and NMDA-R-fEPSP slope from CORT-induced suppressions. A GR→calcineurin pathway is involved in these suppressive effects. The rescue effects by estradiol are driven via ERα or ERß→MAP kinase pathway. Synaptic/extranuclear GR, ERα, and ERß probably participate in these rapid events. Mass-spectrometric analysis determined that acute hippocampal slices used for electrophysiological measurements contained 0.48 nM estradiol less than exogenously applied 1 nM. In vivo physiological level of 8 nM estradiol could protect the intact hippocampus against acute stress-induced neural suppression.

Presence of Three-Dimensional Sound Field Facilitates Listeners' Mood, Felt Emotion, and Respiration Rate When Listening to Music.

Many studies have investigated the effects of music listening from the viewpoint of music features such as tempo or key by measuring psychological or psychophysiological responses. In addition, technologies for three-dimensional sound field (3D-SF) reproduction and binaural recording have been developed to induce a realistic sensation of sound. However, it is still unclear whether music listened to in the presence of 3D-SF is more impressive than in the absence of it. We hypothesized that the presence of a 3D-SF when listening to music facilitates listeners' moods, emotions for music, and physiological activities such as respiration rate. Here, we examined this hypothesis by evaluating differences between a reproduction condition with headphones (HD condition) and one with a 3D-SF reproduction system (3D-SF condition). We used a 3D-SF reproduction system based on the boundary surface control principle (BoSC system) to reproduce a sound field of music in the 3D-SF condition. Music in the 3D-SF condition was binaurally recorded through a dummy head in the BoSC reproduction room and reproduced with headphones in the HD condition. Therefore, music in the HD condition was auditorily as rich in information as that in the 3D-SF condition, but the 3D-sound field surrounding listeners was absent. We measured the respiration rate and heart rate of participants listening to acousmonium and pipe organ music. The participants rated their felt moods before and after they listened to music, and after they listened, they also rated their felt emotion. We found that the increase in respiration rate, the degree of decrease in well-being, and unpleasantness for both pieces in the 3D-SF condition were greater than in the HD condition. These results suggest that the presence of 3D-SF enhances changes in mood, felt emotion for music, and respiration rate when listening to music.

Differential Effects of Focused Attention and Open Monitoring Meditation on Autonomic Cardiac Modulation and Cortisol Secretion.

Mindfulness-based interventions (MBIs) have been used widely as a useful tool for the alleviation of various stress-related symptoms. However, the effects of MBIs on stress-related physiological activity have not yet been ascertained. MBIs primarily consist of focused-attention (FA) and open-monitoring (OM) meditation. Since differing effects of FA and OM meditation on brain activities and cognitive tasks have been mentioned, we hypothesized that FA and OM meditation have also differing effects on stress-related physiological activity. In this study, we examined the effects of FA and OM meditation on autonomic cardiac modulation and cortisol secretion. Forty-one healthy adults (aged 20-46 years) who were meditation novices experienced 30-min FA and OM meditation tasks by listening to instructions. During resting- and meditation-states, electrocardiogram transducers were attached to participants to measure the R-R interval, which were used to evaluate heart rate (HR) and perform heart rate variability (HRV) analyses. Saliva samples were obtained from participants pre- and post-meditation to measure salivary cortisol levels. Results showed that FA meditation induced a decrease in HR and an increase in the root mean square of successive differences (rMSDD). In contrast, OM meditation induced an increase in the standard deviation of the normal-to-normal interval (SDNN) to rMSSD ratio (SDNN/rMSSD) and a decrease in salivary cortisol levels. These results suggest that FA meditation elevates physiological relaxation, whereas OM meditation elevates physiological arousal and reduces stress.

Positive Relationship Between Precompetitive Sympathetic Predominance and Competitive Performance in Elite Extreme Sports Athletes.

Elite athletes achieve superior performance under high pressure in competitive situations. Although it is known that such situations affect the precompetitive activity of their autonomic nervous system (ANS), the relationship between precompetitive ANS activity and performance remains controversial. Especially in extreme sports, it has been shown that cardiac sympathetic tone occurs in athletes before competition attempts. However, the relationship between precompetitive sympathetic tone and performance is unclear. To investigate this relationship in extreme sports, we organized a freestyle snowboard jumping competition and examined competitors' physiological states and performance during this event. The electrocardiograms (ECGs) of 20 elite snowboarders were measured 10 min before each jump in different competitive situations: practice, qualifying, and final sessions. The mean heart rate (HR), the low-frequency to high-frequency component ratio (LF/HF ratio), the logarithm of the HF (lnHF) component of the frequency-domain of the heart rate variability (HRV), the ratio of the standard deviation of all R-R intervals to the root mean square of successive differences of R-R intervals (SDNN/rMSSD ratio), and the rMSSD of the time-domain of the HRV were calculated from the ECG data. The results showed a significant increase in the mean HR as well as significant decreases in the lnHF component and rMSSD of the HRV as the sessions progressed. Interestingly, the mean HR, LF/HF ratio and SDNN/rMSSD ratio of the HRV showed significant positive correlations with competitive scores, and the lnHF component and rMSSD of the HRV showed significant negative correlations with the scores. Our results indicate that precompetitive ANS activity becomes predominantly sympathetic in elite extreme athletes, such as freestyle snowboarders, when the competition intensifies, and that this sympathetic predominance is positively related to competitive performance.

Relationship between oxytocin and maternal approach behaviors to infants' vocalizations.

Infants communicate their emotions to caregivers mainly through vocalizations. Research has shown that maternal oxytocin levels relate to adaptive parenting; however, little empirical research exists regarding the effects of endogenous oxytocin levels on maternal responses to infant vocalizations. Thus, in this study, we examined the relationship between mothers' salivary oxytocin levels, subjective feelings, and behavioral response to infants' emotional vocalizations. Additionally, we examined the relationship between psychological traits and maternal behavioral responses to infant vocalizations. In this study, 39 mothers were asked to stand on a balance board while listening to infant vocalization stimuli, to measure movements of their center of pressure, an index of approach-avoidance behavior. Sixty infant vocalizations (laughter, crying, and neutral) were presented for 6 â€‹s each. Afterwards, participants were asked to rate their subjective responses to each stimulus (not aroused - aroused, displeased - pleased, not urgent - urgent, and healthy - sick). Maternal oxytocin levels were negatively correlated with anterior movement of the center of pressure in response to infants' crying and babbling vocalizations, though no relationship was found between maternal approach-avoidance behavior toward infant laughter and oxytocin levels. This study indicated that maternal approach behavior toward infant vocalizations varies as a function of maternal endogenous oxytocin and the type of infant vocalization.

Differential Effects of Infant Vocalizations on Approach-Avoidance Postural Movements in Mothers.

Infant vocalization plays a pivotal role in communicating infant mood to parents and thereby motivating parenting responses. Although many psychological and neural responses to infant vocalization have been reported, few studies have examined maternal approach-avoidance behavior in response to infant vocalization. Thus, this research sought to determine how infant emotional vocalization affects maternal behavior. Twenty mothers participated in this behavioral study, all of whom had infants of 24 months old or less. In the experiment, they stood on a Balance Board that collected real-time data regarding center of pressure (COP), while listening to a series of infant vocalizations including cry, laugh, and babbling. They then listened to the same vocalizations for a second time and rated their felt emotions in response to each vocalization. The participants demonstrated significant postural movements of approaching in response to cry stimuli or to stimuli regarded as highly urgent. In contrast, they demonstrated postural movement of avoidance in response to laugh vocalization. These findings suggest that parenting behavior in response to infant emotional vocalization is regulated not by the pleasant-unpleasant axis but by the urgency of the stimulus.

Correlation Between Resting Testosterone/Cortisol Ratio and Sound-Induced Vasoconstriction at Fingertip in Men.

A sound-induced sympathetic tone has been used as an index for orienting responses to auditory stimuli. The resting testosterone/cortisol ratio is a biomarker of social aggression that drives an approaching behavior in response to environmental stimuli, and a higher testosterone level and a lower cortisol level can facilitate the sympathetic response to environmental stimuli. Therefore, it is possible that the testosterone/cortisol ratio is correlated with the sound-induced sympathetic tone. The current study investigated the relationship between the resting testosterone/cortisol ratio and vasoconstriction induced by listening to sound stimuli. Twenty healthy males aged 29.0 ± 0.53 years (mean ± S.E.M) participated in the study. They came to the laboratory for 3 days and listened to one of three types of sound stimuli for 1 min on each day. Saliva samples were collected for an analysis of salivary testosterone and cortisol levels on the day of each experiment. After the collecting the saliva sample, we measured the blood volume pulse (BVP) amplitude at a fingertip. Since vasoconstriction is mediated by the activation of the sympathetic nerves, the strength of the reduction in BVP amplitude at a fingertip was called the BVP response (finger BVPR). No difference was observed between the sound-induced finger BVPR for the three types of sound stimuli (p = 0.779). The correlation coefficient between the sound-induced finger BVPR and the salivary testosterone/cortisol ratio within participants was significantly different from no correlation (p = 0.011) and there was a trend toward a significance in the correlation between the sound-induced finger BVPR and the salivary testosterone/cortisol ratio between participants (r = 0.39, p = 0.088). These results suggest that the testosterone/cortisol ratio affects the difference in the sound-evoked sympathetic response.

Heart rate responses induced by acoustic tempo and its interaction with basal heart rate.

Many studies have revealed the influences of music on the autonomic nervous system (ANS). Since previous studies focused on the effects of acoustic tempo on the ANS, and humans have their own physiological oscillations such as the heart rate (HR), the effects of acoustic tempo might depend on the HR. Here we show the relationship between HR elevation induced by acoustic tempo and individual basal HR. Since high tempo-induced HR elevation requires fast respiration, which is based on sympatho-respiratory coupling, we controlled the participants' respiration at a faster rate (20 CPM) than usual (15 CPM). We found that sound stimuli with a faster tempo than the individual basal HR increased the HR. However, the HR increased following a gradual increase in the acoustic tempo only when the extent of the gradual increase in tempo was within a specific range (around + 2%/min). The HR did not follow the increase in acoustic tempo when the rate of the increase in the acoustic tempo exceeded 3% per minute. These results suggest that the effect of the sympatho-respiratory coupling underlying the HR elevation caused by a high acoustic tempo depends on the basal HR, and the strength and the temporal dynamics of the tempo.

Increase in salivary oxytocin and decrease in salivary cortisol after listening to relaxing slow-tempo and exciting fast-tempo music.

Relaxation and excitation are components of the effects of music listening. The tempo of music is often considered a critical factor when determining these effects: listening to slow-tempo and fast-tempo music elicits relaxation and excitation, respectively. However, the chemical bases that underlie these relaxation and excitation effects remain unclear. Since parasympathetic and sympathetic nerve activities are facilitated by oxytocin and glucocorticoid, respectively, we hypothesized that listening to relaxing slow-tempo and exciting fast-tempo music is accompanied by increases in the oxytocin and cortisol levels, respectively. We evaluated the change in the salivary oxytocin and cortisol levels of participants listening to slow-tempo and fast-tempo music sequences. We measured the heart rate (HR) and calculated the heart rate variability (HRV) to evaluate the strength of autonomic nerve activity. After listening to a music sequence, the participants rated their arousal and valence levels. We found that both the salivary oxytocin concentration and the high frequency component of the HRV (HF) increased and the HR decreased when a slow-tempo music sequence was presented. The salivary cortisol level decreased and the low frequency of the HRV (LF) to HF ratio (LF/HF) increased when a fast-tempo music sequence was presented. The ratio of the change in the oxytocin level was correlated with the change in HF, LF/HF and HR, whereas that in the cortisol level did not show any correlation with indices of autonomic nerve activity. There was no correlation between the change in oxytocin level and self-reported emotions, while the change in cortisol level correlated with the arousal level. These findings suggest that listening to slow-tempo and fast-tempo music is accompanied by an increase in the oxytocin level and a decrease in the cortisol level, respectively, and imply that such music listening-related changes in oxytocin and cortisol are involved in physiological relaxation and emotional excitation, respectively.

Sympathetic Tone Induced by High Acoustic Tempo Requires Fast Respiration.

Many studies have revealed the influences of music, and particularly its tempo, on the autonomic nervous system (ANS) and respiration patterns. Since there is the interaction between the ANS and the respiratory system, namely sympatho-respiratory coupling, it is possible that the effect of musical tempo on the ANS is modulated by the respiratory system. Therefore, we investigated the effects of the relationship between musical tempo and respiratory rate on the ANS. Fifty-two healthy people aged 18-35 years participated in this study. Their respiratory rates were controlled by using a silent electronic metronome and they listened to simple drum sounds with a constant tempo. We varied the respiratory rate-acoustic tempo combination. The respiratory rate was controlled at 15 or 20 cycles per minute (CPM) and the acoustic tempo was 60 or 80 beats per minute (BPM) or the environment was silent. Electrocardiograms and an elastic chest band were used to measure the heart rate and respiratory rate, respectively. The mean heart rate and heart rate variability (HRV) were regarded as indices of ANS activity. We observed a significant increase in the mean heart rate and the low (0.04-0.15 Hz) to high (0.15-0.40 Hz) frequency ratio of HRV, only when the respiratory rate was controlled at 20 CPM and the acoustic tempo was 80 BPM. We suggest that the effect of acoustic tempo on the sympathetic tone is modulated by the respiratory system.

Estrogen receptor KO mice study on rapid modulation of spines and long-term depression in the hippocampus.

Rapid modulation of hippocampal synaptic plasticity through synaptic estrogen receptors is an essential topic. We analyzed estradiol-induced modulation of CA1 dendritic spines using adult male ERαKO and ERßKO mice. A 2h treatment of estradiol particularly increased the density of middle-head spines (diameter 0.3-0.4 µm) in wild type mouse hippocampal slices. The enhancement of spinogenesis was completely suppressed by MAP kinase inhibitor. Estradiol-induced increase in middle-head spines was observed in ERßKO mice (which express ERα), but not in ERαKO, indicating that ERα is necessary for the spinogenesis. Direct observation of the dynamic estradiol-induced enhancing effect on rapid spinogenesis was performed using time-lapse imaging of spines in hippocampal live slices from yellow fluorescent protein expressed mice. Both appearance and disappearance of spines occurred, and the number of newly appeared spines was significantly greater than that of disappeared spines, resulting in the net increase of the spine density within 2h. As another type of synaptic modulation, we observed that estradiol rapidly enhanced N-methyl-D-aspartate (NMDA)-induced long-term depression (LTD) in CA1 of the wild type mouse hippocampus. In contrast, estradiol did not enhance NMDA-LTD in ERαKO mice, indicating the involvement of ERα in the estrogen signaling. This article is part of a Special Issue entitled SI: Brain and Memory.

Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: Involvement of kinase networks.

Estradiol (E2) is locally synthesized within the hippocampus in addition to the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. Molecular mechanisms of modulation through synaptic estrogen receptor (ER) and its downstream signaling, however, have been still unknown. We investigated induction of LTP by the presence of E2 upon weak theta burst stimulation (weak-TBS) in CA1 region of adult male hippocampus. Since only weak-TBS did not induce full-LTP, weak-TBS was sub-threshold stimulation. We observed LTP induction by the presence of E2, after incubation of hippocampal slices with 10nM E2 for 30 min, upon weak-TBS. This E2-induced LTP was blocked by ICI, an ER antagonist. This E2-LTP induction was inhibited by blocking Erk MAPK, PKA, PKC, PI3K, NR2B and CaMKII, individually, suggesting that Erk MAPK, PKA, PKC, PI3K and CaMKII may be involved in downstream signaling for activation of NMDA receptors. Interestingly, dihydrotestosterone suppressed the E2-LTP. We also investigated rapid changes of dendritic spines (=postsynapses) in response to E2, using hippocampal slices from adult male rats. We found 1nM E2 increased the density of spines by approximately 1.3-fold within 2h by imaging Lucifer Yellow-injected CA1 pyramidal neurons. The E2-induced spine increase was blocked by ICI. The increase in spines was suppressed by blocking PI3K, Erk MAPK, p38 MAPK, PKA, PKC, LIMK, CaMKII or calcineurin, individually. On the other hand, blocking JNK did not inhibit the E2-induced spine increase. Taken together, these results suggest that E2 rapidly induced LTP and also increased the spine density through kinase networks that are driven by synaptic ER. This article is part of a Special Issue entitled SI: Brain and Memory.

Acute modulation of synaptic plasticity of pyramidal neurons by activin in adult hippocampus.

Activin A is known as a neuroprotective factor produced upon acute excitotoxic injury of the hippocampus (in pathological states). We attempt to reveal the role of activin as a neuromodulator in the adult male hippocampus under physiological conditions (in healthy states), which remains largely unknown. We showed endogenous/basal expression of activin in the hippocampal neurons. Localization of activin receptors in dendritic spines (=postsynapses) was demonstrated by immunoelectron microscopy. The incubation of hippocampal acute slices with activin A (10 ng/mL, 0.4 nM) for 2 h altered the density and morphology of spines in CA1 pyramidal neurons. The total spine density increased by 1.2-fold upon activin treatments. Activin selectively increased the density of large-head spines, without affecting middle-head and small-head spines. Blocking Erk/MAPK, PKA, or PKC prevented the activin-induced spinogenesis by reducing the density of large-head spines, independent of Smad-induced gene transcription which usually takes more than several hours. Incubation of acute slices with activin for 2 h induced the moderate early long-term potentiation (moderate LTP) upon weak theta burst stimuli. This moderate LTP induction was blocked by follistatin, MAPK inhibitor (PD98059) and inhibitor of NR2B subunit of NMDA receptors (Ro25-6981). It should be noted that the weak theta burst stimuli alone cannot induce moderate LTP. These results suggest that MAPK-induced phosphorylation of NMDA receptors (including NR2B) may play an important role for activin-induced moderate LTP. Taken together, the current results reveal interesting physiological roles of endogenous activin as a rapid synaptic modulator in the adult hippocampus.

Sound presentation during different respiration phases alters the sound-induced vasoconstriction mediated by the sympathetic nerve.

The sympathetic orienting response induced by sound has been widely studied and utilized as an index of sound-induced emotions and other mental phenomena. Since sympathetic activity has its own oscillation that is synchronized with the respiration rhythm (sympatho-respiratory coupling), it is possible that the sound-induced orienting response of sympathetic activity varies depending on the respiration phase. In this study, the sound presentations were timed to coincide with the onset of inspiration or expiration. 10 experimental sounds were presented to 12 males aged 21-35 years. Respiration was monitored with an elastic chest band. Vasoconstriction at a finger was measured with laser Doppler flowmetry as a sympathetic orienting response. We found that the sound-induced vasoconstriction was larger for sounds presented in the inspiration phase than for those presented in the expiration phase, suggesting that the respiration network-derived sympathetic tone works as a gate for the sound-induced sympathetic tone.

Habituation of rapid sympathetic response to aversive timbre eliminated by change in basal sympathovagal balance.

We studied the difference in the habituation of the rapid sympathetic response to slightly and highly aversive timbres in 68 males. We measured the decrease in the blood volume pulse amplitude (BVP response) as the rapid sympathetic response and the low- (0.04-0.15 Hz) to high- (0.15-0.40 Hz) frequency (LF/HF) ratio of heart rate variability as the sympathovagal balance. The BVP response was suppressed for slightly aversive timbres that had been presented once before, but not for a highly aversive timbre. In contrast, the prior presentation of a highly aversive timbre enhanced the BVP response to a slightly aversive timbre. Only a highly aversive timbre reduced the LF/HF ratio. We suggest that the lack of habituation of the rapid sympathetic response to an aversive timbre is the result of the balance between the effects of the increase caused by the change in sympathovagal balance to vagal dominance and the decrease caused by classical habituation.

Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen.

The hippocampus synthesizes estrogen and androgen in addition to the circulating sex steroids. Synaptic modulation by hippocampus-derived estrogen or androgen is essential to maintain healthy memory processes. Rapid actions (1-2h) of 17ß-estradiol (17ß-E2) occur via synapse-localized receptors (ERα or ERß), while slow genomic E2 actions (6-48h) occur via classical nuclear receptors (ERα or ERß). The long-term potentiation (LTP), induced by strong tetanus or theta-burst stimulation, is not further enhanced by E2 perfusion in adult rats. Interestingly, E2 perfusion can rescue corticosterone (stress hormone)-induced suppression of LTP. The long-term depression is modulated rapidly by E2 perfusion. Elevation of the E2 concentration changes rapidly the density and head structure of spines in neurons. ERα, but not ERß, drives this enhancement of spinogenesis. Kinase networks are involved downstream of ERα. Testosterone (T) or dihydrotestosterone (DHT) also rapidly modulates spinogenesis. Newly developed Spiso-3D mathematical analysis is used to distinguish these complex effects by sex steroids and kinases. It has been doubted that the level of hippocampus-derived estrogen and androgen may not be high enough to modulate synaptic plasticity. Determination of the accurate concentration of E2, T or DHT in the hippocampus is enabled by mass-spectrometric analysis in combination with new steroid-derivatization methods. The E2 level in the hippocampus is approximately 8nM for the male and 0.5-2nM for the female, which is much higher than that in circulation. The level of T and DHT is also higher than that in circulation. Taken together, hippocampus-derived E2, T, and DHT play a major role in modulation of synaptic plasticity.

Endogenous synthesis of corticosteroids in the hippocampus.

BACKGROUND: Brain synthesis of steroids including sex-steroids is attracting much attention. The endogenous synthesis of corticosteroids in the hippocampus, however, has been doubted because of the inability to detect deoxycorticosterone (DOC) synthase, cytochrome P450(c21). METHODOLOGY/PRINCIPAL FINDINGS: The expression of P450(c21) was demonstrated using mRNA analysis and immmunogold electron microscopic analysis in the adult male rat hippocampus. DOC production from progesterone (PROG) was demonstrated by metabolism analysis of (3)H-steroids. All the enzymes required for corticosteroid synthesis including P450(c21), P450(2D4), P450(11ß1) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) were localized in the hippocampal principal neurons as shown via in situ hybridization and immunoelectron microscopic analysis. Accurate corticosteroid concentrations in rat hippocampus were determined by liquid chromatography-tandem mass spectrometry. In adrenalectomized rats, net hippocampus-synthesized corticosterone (CORT) and DOC were determined to 6.9 and 5.8 nM, respectively. Enhanced spinogenesis was observed in the hippocampus following application of low nanomolar (10 nM) doses of CORT for 1 h. CONCLUSIONS/SIGNIFICANCE: These results imply the complete pathway of corticosteroid synthesis of 'pregnenolone →PROG→DOC→CORT' in the hippocampal neurons. Both P450(c21) and P450(2D4) can catalyze conversion of PROG to DOC. The low nanomolar level of CORT synthesized in hippocampal neurons may play a role in modulation of synaptic plasticity, in contrast to the stress effects by micromolar CORT from adrenal glands.

Hippocampal synthesis of sex steroids and corticosteroids: essential for modulation of synaptic plasticity.

Sex steroids play essential roles in the modulation of synaptic plasticity and neuroprotection in the hippocampus. Accumulating evidence shows that hippocampal neurons synthesize both estrogen and androgen. Recently, we also revealed the hippocampal synthesis of corticosteroids. The accurate concentrations of these hippocampus-synthesized steroids are determined by liquid chromatography-tandem mass-spectrometry in combination with novel derivatization. The hippocampal levels of 17ß-estradiol (E2), testosterone (T), dihydrotestosterone (DHT), and corticosterone (CORT), are 5-15 nM, and these levels are sufficient to modulate synaptic plasticity. Hippocampal E2 modulates memory-related synaptic plasticity not only slowly/genomically but also rapidly/non-genomically. Slow actions of E2 occur via classical nuclear receptors (ERα or ERß), while rapid E2 actions occur via synapse-localized or extranuclear ERα or ERß. Nanomolar concentrations of E2 change rapidly the density and morphology of spines in hippocampal neurons. ERα, but not ERß, drives this enhancement/suppression of spinogenesis in adult animals. Nanomolar concentrations of androgens (T and DHT) and CORT also increase the spine density. Kinase networks are involved downstream of ERα and androgen receptor. Newly developed Spiso-3D mathematical analysis is useful to distinguish these complex effects by sex steroids and kinases. Significant advance has been achieved in investigations of rapid modulation by E2 of the long-term depression or the long-term potentiation.