Effects of electroconvulsive shock on the function, circuitry, and transcriptome of dentate gyrus granule neurons.

Therapeutic use of electroconvulsive shock (ECS) is 75% effective for the remission of treatment-resistant depression. Like other more common forms of antidepressant treatment such as fluoxetine, ECS has been shown to increase neurogenesis in the hippocampal dentate gyrus of rodent models. Yet the question of how ECS-induced neurogenesis supports improvement of depressive symptoms remains unknown. Here, we show that ECS-induced neurogenesis is necessary to improve depressive-like behavior of mice exposed to chronic corticosterone (Cort). We then use slice electrophysiology to show that optogenetic stimulation of adult-born neurons produces a greater hyperpolarization in mature granule neurons after ECS vs Sham treatment. We identify that this hyperpolarization requires the activation of metabotropic glutamate receptor 2 (mGluR2). Consistent with this finding, we observe reduced expression of the immediate early gene cFos in the granule cell layer of ECS vs Sham subjects. We then show that mGluR2 knockdown specifically in ventral granule neurons blunts the antidepressant-like behavioral effects of ECS. Using single nucleus RNA sequencing, we reveal major transcriptomic shifts in granule neurons after treatment with ECS+Cort or fluoxetine+Cort vs Cort alone. We identify a population of immature cells which has greater representation in both ECS+Cort and fluoxetine+Cort treated samples vs Cort alone. We also find global differences in ECS-vs fluoxetine-induced transcriptomic shifts. Together, these findings highlight a critical role for immature granule cells and mGluR2 signaling in the antidepressant action of ECS.

Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Mice.

BACKGROUND: Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, PTSD, dementia, and age-related cognitive decline. While BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis (AHN), its significance as a pharmacological target has not been tested. METHODS: In this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in BPS in mice. RESULTS: Chronic treatment with RO6871135, 7.5 mg/kg increased AHN and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of AHN by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMK2a, CaMK2b, MAP2K6, and GSK3b. An analog compound also demonstrated high affinity for CDK8, CaMK2a, and GSK3b. CONCLUSIONS: These studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS, and points to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.

Posterior cingulate cortex can be a regulatory modulator of the default mode network in task-negative state.

In recent years, the regulation of brain networks and interactions between different brain regions have become important issues in neuroscience. Effective connectivity can be employed to understand the modulatory mechanisms of brain networks. Previous studies have used the task-positive mode to examine effective connectivity between brain regions and very few studies have considered the task-negative mode to explore effective connectivity using electroencephalography (EEG). In the present study, high-density EEG experiments were conducted in 85 participants to measure EEG effective connectivity in relevant default mode network (DMN) brain regions (i.e., the medial prefrontal cortex [mPFC], posterior cingulate cortex [PCC], precuneus, and right frontal and left occipital regions) to observe the effects of different task-negative modes (eyes-open/eyes-closed state) and personality traits (introversion/extroversion). The results showed that in the eyes-closed state, the PCC had significantly increased effective connectivity and played a prominent role as a regulatory modulator of outflow to other regions mediated by alpha rhythms. The mPFC was a regulatory modulator of outflow in the eyes-open state mediated by delta rhythms. The introvert group showed stronger co-modulations in the relevant DMN regions than the extrovert group.

Mismatch negativity impairment is associated with deficits in identifying real-world environmental sounds in schizophrenia.

BACKGROUND: Patients with schizophrenia (SZ) have impairments in processing auditory information that have been linked to deficits in cognitive and psychosocial functioning. Dysfunction in auditory sensory processing in SZ has been indexed by mismatch negativity (MMN), an event-related potential evoked by a rare, deviant stimulus embedded within a sequence of identical standard stimuli. Although MMN deficits in SZ have been studied extensively, relatively little is known about how these deficits relate to accurately identifying real-world, ecologically-salient sounds. METHODS: MMN was assessed in SZ patients (n=21) and non-psychiatric comparison subjects (NCS; n=16). Participants were also assessed in their ability to identify common environmental sounds using a subset of 80 sound clips from the International Affective Digitized Sounds 2nd Ed collection. RESULTS: SZ patients made significantly more errors in environmental sound identification (p<0.001, d=0.86) and showed significantly reduced MMN amplitude deficits in MMN compared to NCS (p<0.01, d=0.97). In SZ patients, MMN deficits were associated with significantly greater environmental sound identification errors (r=0.61, p<0.01). CONCLUSIONS: Impairments in early auditory information processing in schizophrenia account for significant proportions of variance in the ability to identify real-world, functionally relevant environmental sounds. This study supports the view that interventions targeting deficits in low-level auditory sensory processing may also impact more complex cognitive brain processes relevant to psychosocial disability.

Childhood predictors of persistent ADHD in early adulthood: Results from the first follow-up study in China.

It is known that childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood. Previous studies have demonstrated that gender, ADHD symptoms, functional impairment severity, medication treatment, IQ, comorbid with oppositional defiant disorder, conduct disorder and follow-up periods were associated with ADHD persistence in longitudinal samples of western population. In this study, we attempted to widely investigate the predictors particularly in a Chinese Han ADHD cohort. 399 children who met DSM-IV ADHD criteria were followed up into early adulthood. Ordinal logistic regression combined with survival analysis were conducted to examine the association of retrospectively reported childhood factors with adult ADHD persistence based on both categorical indicators and quantitative traits. 46.37% of the participants still met ADHD criteria in adulthood. Logistic models and survival analyses indicated that ADHD combined type appeared as a significant risk factor for ADHD persistence while superior IQ played a protective role even after controlling for the other potential confounders. When quantitative traits were applied, a number of hyperactivity/impulsivity symptoms and IQ still made significant contributions. In conclusion, our results indicated the syndromic continuity of ADHD. Further, a number of hyperactivity/impulsivity symptoms were a risk factor while higher IQ was protective for ADHD persistence.

Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats.

BACKGROUND: In rats, prepulse inhibition (PPI) of acoustic startle is disrupted by systemic administration of dopaminergic agonists, such as the dopamine D3 receptor (D3R)-preferential agonist pramipexole (PPX). PPX has D3R-active (S) and -inactive (R) stereoisomers. Here, we tested the neuroanatomical and stereochemical selectivity of PPX effects on PPI. METHODS: (S)-PRA or (R)-PRA (0, 0.47, 1.42, 4.73 µmol/kg) was injected sc 15 min prior to PPI testing in adult male Sprague Dawley rats. In separate rats, (S)-PPX (0, 3, 10 µg/0.5µl/side, ic) was infused into the nucleus accumbens (NAc), caudodorsal striatum (CS), or olfactory tubercle/Islands of Calleja (ICj) 15 min prior to PPI testing. D3R expression in these brain regions was assessed using quantitative rt-PCR. The PPI-disruptive effects of systemic (S)-PPX were also tested after pretreatment with the D3R-selective antagonist, U99194 (10mg/kg). RESULTS: Systemic administration of PPX stereoisomers demonstrated a dose-dependent effect of (S)-PPX on PPI, while (R)-PPX had no effect on PPI. PPX decreased PPI when infused into the NAc and ICj, but not the CS. Quantitative rt-PCR revealed D3R expression in ICj>NAc>CS. The PPI-disruptive effects of PPX were prevented by U99194. CONCLUSION: The PPI-reducing effects of PPX are stereospecific for the D3R-active (S)-isomer, neuroanatomically preferential for the D3R-rich ventral vs. D3R poor caudodorsal striatum, and prevented by pharmacologic D3R blockade. These findings are consistent with the conclusion that PPX disrupts PPI via stimulation of mesolimbic D3Rs.

Disparate effects of pramipexole on locomotor activity and sensorimotor gating in Sprague-Dawley rats.

Prepulse inhibition (PPI) of acoustic startle and locomotor activity are both widely studied in the preclinical development of dopaminergic agents, including those acting at D3 dopamine receptors. In mice, the dopamine D3 receptor-preferential agonist pramipexole (PPX) alters locomotor activity in a biphasic manner at doses that have no effect on PPI. The present study examined the time-course of PPX effects on locomotion and PPI in rats. In adult male Sprague-Dawley rats, PPX (0, 0.1, 0.3, 1.0mg/kg) was injected prior to measurement of locomotor activity for 90 min in photobeam chambers. Based on disparate early vs. late effects of PPX on locomotion, the effects of PPX (0 vs. 0.3mg/kg) on PPI were tested 20 and 80 min after injection. All doses of PPX decreased locomotor activity for 30 min compared to vehicle, and the higher doses stimulated hyperlocomotion later in the session; the late hyperlocomotion, but not the early hypolocomotion, was blocked by the D2-selective antagonist, L741626 (1.0mg/kg sc). In contrast to its locomotor effects, PPX caused a similar reduction in PPI at 20 and 80 min after administration. These findings suggest both a temporal and pharmacological dissociation between PPX effects on locomotor activity and PPI; these two behavioral measures contribute non-redundant information to the investigation of D3-related behavioral pharmacology.

Parametric approaches towards understanding the effects of the preferential D3 receptor agonist pramipexole on prepulse inhibition in rats.

The preferential dopamine D3 receptor agonist pramipexole (PRA) disrupts prepulse inhibition (PPI) of acoustic startle, an operational measure of sensorimotor gating, in rats. Drug effects on PPI are sensitive to numerous experimental variables; proceeding with in-depth analyses of drug effects without a clear understanding of these variables is inefficient. The present studies characterized the impact on PRA-induced PPI deficits by a range of experimental parameters. As shown previously, PRA reduced both PPI and startle magnitude beginning 5-15 min post-injection; PRA effects on PPI were statistically significant through 35 min post-injection, while those on startle magnitude were still significant 65 min post-injection. PRA-induced PPI deficits were evident under conditions that matched startle magnitude in vehicle and PRA conditions and were independent of PRA-induced changes in prepulse-elicited motor activity. Additionally, PRA-induced PPI deficits did not differ significantly between uni- vs. cross-modal stimuli or between male vs. female rats, with no robust effect of estrous phase in females. These findings demonstrate that PRA effects on PPI are observed across several different experimental conditions and are dissociable from changes in startle magnitude or prepulse-elicited responses. Recommendations are made regarding "optimal" experimental conditions for studying the neurobiology of PRA-induced changes in PPI in rats.

The effects of the dopamine D2 agonist sumanirole on prepulse inhibition in rats.

Dopamine agonists reduce prepulse inhibition (PPI) of startle in rats. While it is used to predict antipsychotic efficacy, the specific receptor subtypes mediating this effect of dopamine agonists remain unclear. We characterized the effects of sumanirole, a highly selective D2 agonist, on PPI in rats. Sumanirole decreased PPI at 60-120 ms prepulse intervals, and increased PPI at 10-20 ms intervals. PPI deficits were antagonized by low doses of the preferential D2 antagonist L741626, supporting a D2 mechanism of action. Sumanirole is a valuable tool for parsing the role of dopamine receptor subtypes in the regulation of PPI.

The effects of pramipexole on prepulse inhibition and locomotor activity in C57BL/6J mice.

Pramipexole (PRA) is a preferential D3R agonist that, in rats and humans, modifies prepulse inhibition (PPI) of the acoustic startle reflex, an operational measure of sensorimotor gating. The ability to use similar PPI measures across species, and the relative ease of genetic manipulations in mice, suggests that molecular studies of the D3R regulation of sensorimotor gating might be best pursued in mice. Here, we evaluate the effects of PRA on PPI and locomotion in C57BL/6J mice, the background strain for many gene knockout mouse models. Male C57BL/6J mice were tested for PPI and locomotor activity after injection of PRA. No significant effects of PRA on PPI were observed at any dose (0.1-10.0 mg/kg), but a significant reduction in startle magnitude was observed after 10 mg/kg PRA. In contrast, the D1/2 agonist, apomorphine (5 mg/kg) significantly reduced PPI in these mice. At doses of PRA that did not alter startle magnitude (0.3, 1, 3 mg/kg), significant decreases in the amount of locomotor and investigatory behavior were observed. Distinct from findings in rats and humans, it seems that either: (i) PRA does not activate D3Rs in C57BL/6J mice, or (ii) D3R agonists are not sufficient to alter PPI in this mouse strain.

Pramipexole effects on startle gating in rats and normal men.

BACKGROUND: Dopamine D3 receptors regulate sensorimotor gating in rats, as evidenced by changes in prepulse inhibition (PPI) of startle after acute administration of D3 agonists and antagonists. In this study, we tested the effects of the D3-preferential agonist, pramipexole, on PPI in normal men and Sprague-Dawley rats. MATERIALS AND METHODS: Acoustic startle and PPI were tested in clinically normal men, comparing the effects of placebo vs. 0.125 mg (n = 20) or placebo vs. 0.1875 mg (n = 20) pramipexole, in double blind, crossover designs. These measures were also tested in male Sprague-Dawley rats using a parallel design [vehicle vs. 0.1 mg/kg (n = 8), vehicle vs. 0.3 mg/kg (n = 8) or vehicle vs. 1.0 mg/kg pramipexole (n = 8)]. Autonomic and subjective measures of pramipexole effects and several personality instruments were also measured in humans. RESULTS: Pramipexole increased drowsiness and significantly increased PPI at 120-ms intervals in humans; the latter effect was not moderated by baseline PPI or personality scale scores. In rats, pramipexole causes a dose-dependent reduction in long-interval (120 ms) PPI, while low doses actually increased short-interval (10-20 ms) PPI. Effects of pramipexole on PPI in rats were independent of baseline PPI and changes in startle magnitude. CONCLUSION: The preferential D3 agonist pramipexole modifies PPI in humans and rats. Unlike indirect DA agonists and mixed D2/D3 agonists, pramipexole increases long-interval PPI in humans, in a manner that is independent of baseline PPI and personality measures. These findings are consistent with preclinical evidence for differences in the D2- and D3-mediated regulation of sensorimotor gating.

Using prepulse inhibition to detect functional D3 receptor antagonism: effects of WC10 and WC44.

Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia. Treatment with mixed dopamine D2/D3 antagonists diminishes schizophrenia symptoms, and opposes dopamine agonist-induced PPI deficits in rats. There are reasons to believe that functional D3 receptor antagonists might offer more favorable therapeutic profiles compared to current antipsychotics. However, D3-related drug discovery is hampered by the absence of assays sensitive to D3-mediated (antipsychotic) properties in vivo. Here, we characterized two putative D3-active compounds - WC10 and WC44 - in a PPI-based screening assay, comparing the sensitivity of test compounds to oppose PPI deficits induced by the mixed D1/D2-like agonist apomorphine vs. the preferential D3 agonist pramipexole in rats. WC10, WC44 (0, 1, 3, 10 mg/kg, each), and the preferential D2 antagonist L741,626 (0, 1 mg/kg) were studied, in combination with apomorphine (0, 0.5 mg/kg), or pramipexole (0, 1 mg/kg). L741,626 prevented apomorphine-, but not pramipexole-induced PPI deficits. WC10, but not WC44, prevented apomorphine-induced PPI deficits; both compounds opposed pramipexole-induced PPI deficits, suggesting functional D3 and D1/D2 antagonist profiles for WC10, and functional D3 receptor antagonism for WC44. This assay may be valuable for detecting predominantly D3 vs. D2 receptor-linked mechanisms of action in vivo.

Normal human aging and early-stage schizophrenia share common molecular profiles.

We examined genome-wide expression datasets from human prefrontal cortex of normal and schizophrenic individuals ranging from 19 to 81 years of age. We found that changes in gene expression that are correlated with aging in normal subjects differ dramatically from those observed with aging in schizophrenic subjects. Only 2.5% of genes were correlated with age in both groups. Surprisingly, we also found a significant overlap (29-34%) between those genes whose expression was correlated with aging in normal subjects and those significantly altered in subjects with early-stage schizophrenia (within 4 years of diagnosis). This suggests that schizophrenia onset anticipates the normal aging process, and further, that some symptoms of aging, i.e. dementia and psychosis, might be explained by these common molecular profiles.

Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation.

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is deficient in several brain disorders and is disrupted in rats by dopamine (DA) agonists. Robust heritable strain differences are observed between Sprague-Dawley (SD) and Long-Evans (LE) strains in sensitivity to the PPI-disruptive effects of DA agonists associated with differential gene expression in the nucleus accumbens. Here, we compared the contribution of D2 versus D3 receptors with this heritable difference, using the D3-preferential agonist (pramipexole), the mixed D3/D2 agonist (quinpirole), the mixed D1/D2-like agonist (apomorphine), and the preferential D2 antagonist (L741,626). All DA agonists disrupted PPI in SD and LE rats. Greater sensitivity for this effect was evident with apomorphine and quinpirole in SD than LE rats, but not with pramipexole. The selective D2 antagonist L741,626 preferentially reversed apomorphine-induced PPI deficits at a dose that did not alter pramipexole-induced PPI deficits. We conclude that the heritable pattern of greater PPI 'disruptability' by DA agonists in SD versus LE rats reflects differences in D2 but not D3 receptor-associated mechanisms.

Genetic contributions to white matter architecture revealed by diffusion tensor imaging in Williams syndrome.

Little is known about genetic regulation of the development of white matter. This knowledge is critical in understanding the pathophysiology of neurodevelopmental syndromes associated with altered cognition as well as in elucidating the genetics of normal human cognition. The hemideletion of approximately 25 genes on chromosome 7q11.23 that causes Williams syndrome (WS) includes genes that regulate cytoskeletal dynamics in neurons, especially LIMK1 and CYLN2, and therefore offers the opportunity to investigate the role of these genes in the formation of white matter tracts. We used diffusion tensor imaging to demonstrate alteration in white matter fiber directionality, deviation in posterior fiber tract course, and reduced lateralization of fiber coherence in WS. These abnormalities are consistent with an alteration of the late stages of neuronal migration, define alterations of white matter structures underlying dissociable behavioral phenotypes in WS, and provide human in vivo information about genetic control of white matter tract formation.

Meta-analysis of neuroimaging studies of the Wisconsin card-sorting task and component processes.

A quantitative meta-analysis using the activation likelihood estimation (ALE) method was used to investigate the brain basis of the Wisconsin Card-Sorting Task (WCST) and two hypothesized component processes, task switching and response suppression. All three meta-analyses revealed distributed frontoparietal activation patterns consistent with the status of the WCST as an attention-demanding executive task. The WCST was associated with extensive bilateral clusters of reliable cross-study activity in the lateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobule. Task switching revealed a similar, although less robust, frontoparietal pattern with additional clusters of activity in the opercular region of the ventral prefrontal cortex, bilaterally. Response-suppression tasks, represented by studies of the go/no-go paradigm, showed a large and highly right-lateralized region of activity in the right prefrontal cortex. The activation patterns are interpreted as reflecting a neural fractionation of the cognitive components that must be integrated during the performance of the WCST.