Decreased thalamo-cortico connectivity during an implicit sequence motor learning task and 7 days escitalopram intake.

Evidence suggests that selective serotonin reuptake inhibitors (SSRIs) reorganize neural networks via a transient window of neuroplasticity. While previous findings support an effect of SSRIs on intrinsic functional connectivity, little is known regarding the influence of SSRI-administration on connectivity during sequence motor learning. To investigate this, we administered 20 mg escitalopram or placebo for 1-week to 60 healthy female participants undergoing concurrent functional magnetic resonance imaging and sequence motor training in a double-blind randomized controlled design. We assessed task-modulated functional connectivity with a psycho-physiological interaction (PPI) analysis in the thalamus, putamen, cerebellum, dorsal premotor, primary motor, supplementary motor, and dorsolateral prefrontal cortices. Comparing an implicit sequence learning condition to a control learning condition, we observed decreased connectivity between the thalamus and bilateral motor regions after 7 days of escitalopram intake. Additionally, we observed a negative correlation between plasma escitalopram levels and PPI connectivity changes, with higher escitalopram levels being associated with greater thalamo-cortico decreases. Our results suggest that escitalopram enhances network-level processing efficiency during sequence motor learning, despite no changes in behaviour. Future studies in more diverse samples, however, with quantitative imaging of neurochemical markers of excitation and inhibition, are necessary to further assess neural responses to escitalopram.

Efficacy of preclinical pharmacological interventions against alterations of neuronal network oscillations in Alzheimer's disease: A systematic review.

Despite the development of multiple pharmacological approaches over the years aimed at treating Alzheimer's Disease (AD) only very few have been approved for clinical use in patients. To date there still exists no disease-modifying treatment that could prevent or rescue the cognitive impairment, particularly of memory aquisition, that is characteristic of AD. One of the possibilities for this state of affairs might be that the majority of drug discovery efforts focuses on outcome measures of decreased neuropathological biomarkers characteristic of AD, without taking into acount neuronal processes essential to the generation and maintenance of memory processes. Particularly, the capacity of the brain to generate theta (θ) and gamma (γ) oscillatory activity has been strongly correlated to memory performance. Using a systematic review approach, we synthesize the existing evidence in the literature on pharmacological interventions that enhance neuronal theta (θ) and/or gamma (γ) oscillations in non-pathological animal models and in AD animal models. Additionally, we synthesize the main outcomes and neurochemical systems targeted. We propose that functional biomarkers such as cognition-relevant neuronal network oscillations should be used as outcome measures during the process of research and development of novel drugs against cognitive impairment in AD.

Structural alterations in cortical and thalamocortical white matter tracts after recovery from prefrontal cortex lesions in macaques.

Unilateral damage to the frontoparietal network typically impairs saccade target selection within the contralesional visual hemifield. Severity of deficits and the degree of recovery have been associated with widespread network dysfunction, yet it is not clear how these behavioural and functional brain changes relate with the underlying structural white matter tracts. Here, we investigated whether recovery after unilateral prefrontal cortex (PFC) lesions was associated with changes in white matter microstructure across large-scale frontoparietal cortical and thalamocortical networks. Diffusion-weighted imaging was acquired in four male rhesus macaques at pre-lesion, week 1, and week 8-16 post-lesion when target selection deficits largely recovered. Probabilistic tractography was used to reconstruct cortical frontoparietal fiber tracts, including the superior longitudinal fasciculus (SLF) and transcallosal fibers connecting the PFC or posterior parietal cortex (PPC), as well as thalamocortical fiber tracts connecting the PFC and PPC to thalamic nuclei. We found that the two animals with small PFC lesions showed increased fractional anisotropy in both cortical and thalamocortical fiber tracts when behaviour had recovered. However, we found that fractional anisotropy decreased in cortical frontoparietal tracts after larger PFC lesions yet increased in some thalamocortical tracts at the time of behavioural recovery. These findings indicate that behavioural recovery after small PFC lesions may be supported by both cortical and subcortical areas, whereas larger PFC lesions may have induced widespread structural damage and hindered compensatory remodeling in the cortical frontoparietal network.

Executive functioning-specific behavioral impairments in a rat model of human third trimester binge drinking implicate prefrontal-thalamo-hippocampal circuitry in Fetal Alcohol Spectrum Disorders.

Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impairments in executive functioning (EF). Specifically, the domains of working memory, inhibition, and set shifting are frequently impacted by prenatal alcohol exposure. Coordination between prefrontal cortex and hippocampus appear to be essential for these domains of executive functioning. The current study uses a rodent model of human third-trimester binge drinking to identify the extent of persistent executive functioning deficits following developmental alcohol by using a behavioral battery of hippocampus- and prefrontal cortex-dependent behavioral assays in adulthood. Alcohol added to milk formula was administered to Long Evans rat pups on postnatal days 4-9 (5.25 g/kg/day of ethanol; intragastric intubation), a period when rodent brain development undergoes comparable processes to human third-trimester neurodevelopment. Procedural control animals underwent sham intubation, without administration of any liquids (i.e., alcohol, milk solution). In adulthood, male rats were run on a battery of behavioral assays: novel object recognition, object-in-place associative memory, spontaneous alternation, and behavioral flexibility tasks. Alcohol-exposed rats demonstrated behavioral impairment in object-in-place preference and performed worse when the rule was switched on a plus maze task. All rats showed similar levels of novel object recognition, spontaneous alternation, discrimination learning, and reversal learning, suggesting alcohol-induced behavioral alterations are selective to executive functioning domains of spatial working memory and set-shifting in this widely-utilized rodent model. These specific behavioral alterations support the hypothesis that behavioral impairments in EF following prenatal alcohol exposure are caused by distributed damage to the prefrontal-thalamo-hippocampal circuit consisting of the medial prefrontal cortex, thalamic nucleus reuniens, and CA1 of hippocampus.

Organophosphate Flame Retardants Excite Arcuate Melanocortin Circuitry and Increase Neuronal Sensitivity to Ghrelin in Adult Mice.

Organophosphate flame retardants (OPFRs) are a class of chemicals that have become near ubiquitous in the modern environment. While OPFRs provide valuable protection against flammability of household items, they are increasingly implicated as an endocrine disrupting chemical (EDC). We previously reported that exposure to a mixture of OPFRs causes sex-dependent disruptions of energy homeostasis through alterations in ingestive behavior and activity in adult mice. Because feeding behavior and energy expenditure are largely coordinated by the hypothalamus, we hypothesized that OPFR disruption of energy homeostasis may occur through EDC action on melanocortin circuitry within the arcuate nucleus. To this end, we exposed male and female transgenic mice expressing green fluorescent protein in either neuropeptide Y (NPY) or proopiomelanocortin (POMC) neurons to a common mixture of OPFRs (triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl)phosphate; each 1 mg/kg bodyweight/day) for 4 weeks. We then electrophysiologically examined neuronal properties using whole-cell patch clamp technique. OPFR exposure depolarized the resting membrane of NPY neurons and dampened a hyperpolarizing K+ current known as the M-current within the same neurons from female mice. These neurons were further demonstrated to have increased sensitivity to ghrelin excitation, which more potently reduced the M-current in OPFR-exposed females. POMC neurons from female mice exhibited elevated baseline excitability and are indicated in receiving greater excitatory synaptic input when exposed to OPFRs. Together, these data support a sex-selective effect of OPFRs to increase neuronal output from the melanocortin circuitry governing feeding behavior and energy expenditure, and give reason for further examination of OPFR impact on human health.

Central effects of erenumab in migraine patients: An event-related functional imaging study.

OBJECTIVE: To determine whether erenumab, a new monoclonal antibody to the calcitonin gene-related peptide (CGRP) receptor, exerts functional central effects in migraineurs by performing functional imaging scans on patients treated with erenumab. METHODS: We conducted an fMRI study on 27 patients with migraine using a well-established trigeminal nociceptive paradigm, examining patients before and 2 weeks after administration of the CGRP receptor antibody erenumab 70 mg. RESULTS: Comparing both visit days in all patients (n = 27) revealed that erenumab leads to a decrease in activation in the right thalamus (i.e., contralateral to the stimulated side), right middle temporal gyrus, right lingual gyrus, left operculum, and several clusters on both sides of the cerebellum. Furthermore, when responders (n = 9) and nonresponders (n = 8) of the respective same headache state were compared, we found a significant reduction of hypothalamic activation after the administration of erenumab in responders only (t = 4.78; contrast estimate 29.79 [90% confidence interval 19.53-40.05]). This finding of reduced hypothalamic activation was confirmed when absolute headache days was used as a regressor. INTERPRETATION: These findings suggest that erenumab may not be an exclusively peripheral migraine treatment but has additional central effects. Whether this is due to secondary changes after peripheral modulation of sensory input or indeed represents a direct central mode of action is discussed.

Acute pharmacological inhibition of matrix metalloproteinase-9 activity during development restores perineuronal net formation and normalizes auditory processing in Fmr1 KO mice.

Individuals with Fragile X Syndrome (FXS) and autism spectrum disorder (ASD) exhibit cognitive impairments, social deficits, increased anxiety, and sensory hyperexcitability. Previously, we showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to abnormal development of parvalbumin (PV) interneurons and perineuronal nets (PNNs) in the developing auditory cortex (AC) of Fmr1 knock-out (KO) mice, which likely underlie auditory hypersensitivity. Thus, MMP-9 may serve as a potential target for treatment of auditory hypersensitivity in FXS. Here, we used the MMP-2/9 inhibitor, SB-3CT, to pharmacologically inhibit MMP-9 activity during a specific developmental period and to test whether inhibition of MMP-9 activity reverses neural oscillation deficits and behavioral impairments by enhancing PNN formation around PV cells in Fmr1 KO mice. Electroencephalography (EEG) was used to measure resting state and sound-evoked electrocortical activity in auditory and frontal cortices of postnatal day (P)22-23 male mice before and one-day after treatment with SB-3CT (25 mg/kg) or vehicle. At P27-28, animal behaviors were tested to measure the effects of the treatment on anxiety and hyperactivity. Results show that acute inhibition of MMP-9 activity improved evoked synchronization to auditory stimuli and ameliorated mouse behavioral deficits. MMP-9 inhibition enhanced PNN formation, increased PV levels and TrkB phosphorylation yet reduced Akt phosphorylation in the AC of Fmr1 KO mice. Our results show that MMP-9 inhibition during early postnatal development is beneficial in reducing some auditory processing deficits in the FXS mouse model and may serve as a candidate therapeutic for reversing sensory hypersensitivity in FXS and possibly other ASDs.

Intrinsic connections between thalamic sub-regions and the lateral prefrontal cortex are differentially impacted by acute methylphenidate.

BACKGROUND: The thalamus is a major target of dopaminergic projections and is densely connected with the prefrontal cortex. A better understanding of how dopamine changes thalamo-cortical communication may shed light on how dopamine supports cognitive function. Methylphenidate has been shown to facilitate cognitive processing and reduce connectivity between the thalamus and lateral prefrontal cortex. AIMS: The thalamus is a heterogeneous structure, and the present study sought to clarify how the intrinsic connections of thalamic sub-regions are differentially impacted by acute dopamine transporter blockade. METHODS: Sixty healthy volunteers were orally administered either 20 mg of methylphenidate (N = 29) or placebo (N = 31) in a double-blind, randomized, between-subject design. Multi-echo fMRI was used to assess intrinsic functional connectivity of sub-regions of the thalamus during a resting state scan. An N-back working-memory paradigm provided a measure of cognitive performance. RESULTS: Acute methylphenidate significantly reduced connectivity of the lateral prefrontal cortex with the motor and somatosensory sub-regions of the thalamus and reduced connectivity with the parietal and visual sub-regions at a trend level. Connectivity with the premotor, prefrontal, and temporal sub-regions was not impacted. The intrinsic connectivity between the thalamus and the lateral prefrontal cortex was not associated with working-memory performance. CONCLUSIONS: Methylphenidate decreases functional connections between the lateral prefrontal cortex and thalamus broadly, while sparing intrinsic connectivity with thalamic sub-regions involved with working-memory and language related processes. Collectively, our results suggest that the dopamine transporter regulates functional connections between the prefrontal cortex and non-cognitive areas of the thalamus.

Basolateral amygdala - nucleus accumbens circuitry regulates optimal cue-guided risk/reward decision making.

Maladaptive decision making is a characteristic feature of substance use disorder and pathological gambling. Studies in humans and animals have implicated neural circuits that include the basolateral amygdala (BLA) and nucleus accumbens (NAc) in facilitating risk/reward decision making. However, the preclinical literature has focussed primarily on situations where animals use internally-generated information to adapt to changes in reward likelihood, whereas many real-life situations require the use of external stimuli to facilitate context-appropriate behavior. We recently developed the "Blackjack" task, to measure cued risk/reward decision making requiring rats to chose between Small/Certain and Large/Risky rewards, with auditory cues at the start of each trial explicitly informing that the probability of obtaining a large reward was either good (50%) or poor (12.5%). Here we investigated the contribution of the BLA and its interaction with the NAc in guiding these types of decisions. In well-trained male rats, bilateral inactivation of the BLA induced suboptimal decision making, primarily by reducing risky choice on good-odds trials. In comparison, pharmacological disconnection of the BLA and NAc-shell also induced suboptimal decision making, diverting choice from more preferred option by reducing or increasing risky choice on good vs. poor odds trials respectively. Together, these results suggest that the BLA-NAc circuitry plays a crucial role in integrating information provided by discriminative stimuli. Furthermore, this circuitry may aid in guiding action selection of advantageous options in situations to maximize rewards. Finally, they suggest that perturbations in optimal decision making observed in substance abuse and gambling disorders may be driven in part by dysfunction within this circuitry.

Concentration-response evaluation of ToxCast compounds for multivariate activity patterns of neural network function.

The US Environmental Protection Agency's ToxCast program has generated toxicity data for thousands of chemicals but does not adequately assess potential neurotoxicity. Networks of neurons grown on microelectrode arrays (MEAs) offer an efficient approach to screen compounds for neuroactivity and distinguish between compound effects on firing, bursting, and connectivity patterns. Previously, single concentrations of the ToxCast Phase II library were screened for effects on mean firing rate (MFR) in rat primary cortical networks. Here, we expand this approach by retesting 384 of those compounds (including 222 active in the previous screen) in concentration-response across 43 network activity parameters to evaluate neural network function. Using hierarchical clustering and machine learning methods on the full suite of chemical-parameter response data, we identified 15 network activity parameters crucial in characterizing activity of 237 compounds that were response actives ("hits"). Recognized neurotoxic compounds in this network function assay were often more potent compared to other ToxCast assays. Of these chemical-parameter responses, we identified three k-means clusters of chemical-parameter activity (i.e., multivariate MEA response patterns). Next, we evaluated the MEA clusters for enrichment of chemical features using a subset of ToxPrint chemotypes, revealing chemical structural features that distinguished the MEA clusters. Finally, we assessed distribution of neurotoxicants with known pharmacology within the clusters and found that compounds segregated differentially. Collectively, these results demonstrate that multivariate MEA activity patterns can efficiently screen for diverse chemical activities relevant to neurotoxicity, and that response patterns may have predictive value related to chemical structural features.

Dietary phytoestrogens modulate aggression and activity in social behavior circuits of male mice.

Phytoestrogens comprise biologically active constituents of human and animal diet that can impact on systemic and local estrogen functions in the brain. Here we report on the importance of dietary phytoestrogens for maintaining activity in a brain circuit controlling aggressive and social behavior of male mice. After six weeks of low-phytoestrogen chronic diet (diadzein plus genistein <20 µg/g) a reduction of intermale aggression and altered territorial marking behavior could be observed, compared to littermates on a standard soy-bean based diet (300 µg/g). Further, mice on low-phyto diet displayed a decrease in sociability and a reduced preference for social odors, indicating a general disturbance of social behavior. Underlying circuits were investigated by analysing the induction of the activity marker c-Fos upon social encounter. Low-phyto diet led to a markedly reduced c-Fos induction in the medial as well as the cortical amygdala, the lateral septum, medial preoptic area and bed nucleus of the stria terminalis. No difference between groups was observed in the olfactory bulb. Together our data suggest that dietary phytoestrogens critically modulate social behavior circuits in the male mouse brain.

Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion.

2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/- mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic "rich club" and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic "rich club" regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/- mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent.

Premotor Cortical-Cerebellar Reorganization in a Macaque Model of Primary Motor Cortical Lesion and Recovery.

Neuromotor systems have the capacity for functional recovery following local damage. The literature suggests a possible role for the premotor cortex and cerebellum in motor recovery. However, the specific changes to interactions between these areas following damage remain unclear. Here, we demonstrate potential rewiring of connections from the ipsilesional ventral premotor cortex (ip-PMv) to cerebellar structures in a nonhuman primate model of primary motor cortex (M1) lesion and motor recovery. Cerebellar connections arising from the ip-PMv were investigated by comparing biotinylated dextran amine (BDA) between two groups of male Macaca mulatta: M1-lesion/motor recovery group and intact group. There were more BDA-labeled boutons and axons in all ipsilesional deep cerebellar nuclei (fastigial, interposed, and dentate) in the M1-lesion/recovery group than in the intact group. The difference was evident in the ipsilesional fastigial nucleus (ip-FN), and particularly observed in its middle, a putative somatosensory region of the ip-FN, which was characterized by absent or little expression of aldolase C. Some of the altered projections from the ip-PMv to ip-FN neurons were confirmed as functional because the synaptic markers, synaptophysin and vesicular glutamate transporter 1, were colocalized with BDA-labeled boutons. These results suggest that the adult primate brain after motor lesions can reorganize large-scale networks to enable motor recovery by enhancing sensorimotor coupling and motor commands via rewired fronto-cerebellar connections.SIGNIFICANCE STATEMENT Damaging the motor cortex causes motor deficits, which can be recovered over time. Such motor recovery may result from functional compensation in remaining neuromotor areas, including the ventral premotor cortex. We investigated compensatory changes in neural axonal outputs from ventral premotor to deep cerebellar nuclei in a monkey model of primary motor cortical lesion and motor recovery. The results showed an increase in premotor projections and synaptic formations in deep cerebellar nuclei, especially the sensorimotor region of the fastigial nucleus. Our results provide the first evidence that large-scale reorganization of fronto-cerebellar circuits may underlie functional recovery after motor cortical lesions.

Differences between ketamine's short-term and long-term effects on brain circuitry in depression.

Ketamine acts as a rapid clinical antidepressant at 25 min after injection with effects sustained for 7 days. As dissociative effects emerging acutely after injection are not entirely discernible from therapeutic action, we aimed to dissect the differences between short-term and long-term response to ketamine to elucidate potential imaging biomarkers of ketamine's antidepressant effect. We used a genetical model of depression, in which we bred depressed negative cognitive state (NC) and non-depressed positive cognitive state (PC) rat strains. Four parallel rat groups underwent stress-escape testing and a week later received either S-ketamine (12 NC, 13 PC) or saline (12 NC, 12 PC). We acquired resting-state functional magnetic resonance imaging time series before injection and at 30 min and 48 h after injection. Graph analysis was used to calculate brain network properties. We identified ketamine's distinct action over time in a qualitative manner. The rapid response entailed robust and strain-independent topological modifications in cognitive, sensory, emotion, and reward-related circuitry, including regions that exhibited correlation of connectivity metrics with depressive behavior, and which could explain ketamine's dissociative and antidepressant properties. At 48 h ketamine had mainly strain-specific action normalizing habenula, midline thalamus, and hippocampal connectivity measures in depressed rats. As these nodes mediate cognitive flexibility impaired in depression, action within this circuitry presumably reflects ketamine's procognitive effects induced only in depressed patients. This finding is especially valid, as our model represents cognitive aspects of depression. These empirically defined circuits explain ketamine's distinct action over time and might serve as translational imaging correlates of antidepressant response in preclinical testing.

Engineering brain activity patterns by neuromodulator polytherapy for treatment of disorders.

Conventional drug screens and treatments often ignore the underlying complexity of brain network dysfunctions, resulting in suboptimal outcomes. Here we ask whether we can correct abnormal functional connectivity of the entire brain by identifying and combining multiple neuromodulators that perturb connectivity in complementary ways. Our approach avoids the combinatorial complexity of screening all drug combinations. We develop a high-speed platform capable of imaging more than 15000 neurons in 50ms to map the entire brain functional connectivity in large numbers of vertebrates under many conditions. Screening a panel of drugs in a zebrafish model of human Dravet syndrome, we show that even drugs with related mechanisms of action can modulate functional connectivity in significantly different ways. By clustering connectivity fingerprints, we algorithmically select small subsets of complementary drugs and rapidly identify combinations that are significantly more effective at correcting abnormal networks and reducing spontaneous seizures than monotherapies, while minimizing behavioral side effects. Even at low concentrations, our polytherapy performs superior to individual drugs even at highest tolerated concentrations.

Cholinergic and serotonergic modulation of resting state functional brain connectivity in Alzheimer's disease.

Disruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness of these systems in AD we measured the effects of a single-dose of the selective serotonin reuptake inhibitor citalopram and acetylcholinesterase inhibitor galantamine in 12 patients with AD and 12 age-matched controls on functional brain connectivity with resting state functional magnetic resonance imaging. In this randomized, double blind, placebo-controlled crossover study, functional magnetic resonance images were repeatedly obtained before and after dosing, resulting in a dataset of 432 scans. Connectivity maps of ten functional networks were extracted using a dual regression method and drug vs. placebo effects were compared between groups with a multivariate analysis with signals coming from cerebrospinal fluid and white matter as covariates at the subject level, and baseline and heart rate measurements as confound regressors in the higher-level analysis (at p < 0.05, corrected). A galantamine induced difference between groups was observed for the cerebellar network. Connectivity within the cerebellar network and between this network and the thalamus decreased after galantamine vs. placebo in AD patients, but not in controls. For citalopram, voxelwise network connectivity did not show significant group × treatment interaction effects. However, we found default mode network connectivity with the precuneus and posterior cingulate cortex to be increased in AD patients, which could not be detected within the control group. Further, in contrast to the AD patients, control subjects showed a consistent reduction in mean connectivity with all networks after administration of citalopram. Since AD has previously been characterized by reduced connectivity between the default mode network and the precuneus and posterior cingulate cortex, the effects of citalopram on the default mode network suggest a restoring potential of selective serotonin reuptake inhibitors in AD. The results of this study also confirm a change in cerebellar connections in AD, which is possibly related to cholinergic decline.

Synapse-specific opioid modulation of thalamo-cortico-striatal circuits.

The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.

Comparison of Actions between L-DOPA and Different Dopamine Agonists in Striatal DA-Depleted Microcircuits In Vitro: Pre-Clinical Insights.

Parkinson's disease (PD) is a neurodegenerative illness presenting motor and non-motor symptoms due to the loss of dopaminergic terminals in basal ganglia, most importantly, the striatum. L-DOPA relieves many motor signs. Unfortunately, in the long term, L-DOPA use causes motor disabilities by itself and does not act in comorbid conditions such as depression. These deficiencies have led to search for drugs such as dopamine (DA) receptor agonists (DA-agonists) that allow the reduction of L-DOPA dose. Previously, we have identified the attributes of non-stimulated (resting) and cortical stimulated (active) striatal microcircuits following the activity of dozens of neurons simultaneously using calcium imaging in brain slices. We also have characterized the changes that take place in DA-depleted microcircuits in vitro. In control conditions, there is low spontaneous activity. After cortical stimulation (CtxS) sequences and alternation of neuronal ensembles activity occur, including reverberations. In contrast, DA-deprived circuits exhibit high spontaneous activity at rest, and a highly recurrent ensemble curtails alternation. Interestingly, CtxS briefly relieves these Parkinsonian signs in DA-depleted tissue. Here we compare the actions of some DA-agonists used in PD therapeutics on the pathological dynamics of DA-depleted microcircuits at rest and with CtxS; taking L-DOPA as reference. D2-class agonists better reduce the excessive spontaneous activity of DA-depleted microcircuits. All DA-agonists tend to maintain ensemble alternation seen in control circuits after CtxS. However, quantitative analyses suggest differences in their actions: in general, DA-agonists only approximate L-DOPA actions. Nonetheless no treatment, including L-DOPA, completely restores microcircuit dynamics to control conditions.

Ginkgo biloba treatments reverse the impairment of conditioned suppression acquisition induced by GluN2B-NMDA and 5-HT1A receptor blockade: Modulatory effects of the circuitry of the dorsal hippocampal formation.

To improve our understanding of the effects of standardized extract of Ginkgo biloba (EGb) as a cognitive enhancer, we investigated the conditioned lick suppression-induced expression (mRNA and protein) of the GluN2B-containing N-methyl-D-aspartic acid receptor (GluN2B-NMDAR), serotonin (5-HT) 1A receptor (5-HT1AR), gamma-aminobutyric acid type A receptor (GABAAR) and glial fibrillary acidic protein (GFAP) in the dorsal hippocampal formation (dHF) of untreated and EGb-treated (0.25, 0.5 and 1.0 g.kg-1) groups of rats. To substantiate our data, we analysed the molecular changes in dHF following treatment with vehicle, with agonists or antagonists of GABAAR, GluN2B-NMDAR and 5-HT1AR or with one of these antagonists prior to EGb and fear memory acquisition. Additionally, we performed a pharmacological analysis of the drug-receptor-receptor interactions and their supplemental role in fear memory by blocking individual receptors and analysed the possible changes in expression level with each of the other receptors in the study as well as astrocytes. Our data show for the first time that EGb treatment not only upregulated GluN2B, GABAAR-α5, and GFAP compared with the control but also differentially upregulated GABAAR-α1 in the dHF and 5HT1AR in the CA3. We found that the activation of GABAARs (diazepam) and the inactivation of GluN2B-NMDARs (Ro25-6981) or 5-HT1AR ((S)-WAY100135) resulted in memory impairment. Further, higher doses of EGb treatment reversed the effect of blocking GluN2B (P < 0.001) and 5-HT1AR (P < 0.001). Here, treatment with Ro25-6981 + EGb or (S)-WAY100135 + EGb prevented the impairment of the acquisition of lick suppression in association with the upregulation or prevention of the downregulation of Grin2b expression as well as the expression of GluN2B-NMDA and/or α1 and α5 subunit-containing GABAAR in the CA1 (P < 0.0001). Our data are in line with previous findings concerning the necessity of GluN2B for fear memory formation and add to the current knowledge of the role of the GABAAR-α1 and -α5 subunits and of GluN2B as a target of cognitive enhancers. Furthermore, our data show that these receptors play a complementary role in controlling the neural circuitry in the dHF that seems to be essential to conditioned lick suppression and the modulatory effects of EGb.

Pubertal development of estradiol-induced hypothalamic progesterone synthesis.

In females, a hallmark of puberty is the luteinizing hormone (LH) surge that triggers ovulation. Puberty initiates estrogen positive feedback onto hypothalamic circuits, which underlie the stimulation of gonadotropin releasing hormone (GnRH) neurons. In reproductively mature female rodents, both estradiol (E2) and progesterone (P4) signaling are necessary to stimulate the surge release of GnRH and LH. Estradiol membrane-initiated signaling facilitates progesterone (neuroP) synthesis in hypothalamic astrocytes, which act on E2-induced progesterone receptors (PGR) to stimulate kisspeptin release, thereby activating GnRH release. How the brain changes during puberty to allow estrogen positive feedback remains unknown. In the current study, we hypothesized that a critical step in estrogen positive feedback was the ability for estradiol-induced neuroP synthesis. To test this idea, hypothalamic neuroP levels were measured in groups of prepubertal, pubertal and young adult female Long Evans rats. Steroids were measured with liquid chromatography tandem mass spectrometry (LC-MS/MS). Hypothalamic neuroP increases from pre-puberty to young adulthood in both gonad-intact females and ovariectomized rats treated with E2. The pubertal development of hypothalamic E2-facilitated progesterone synthesis appears to be one of the neural switches facilitating reproductive maturation.