Oral ketamine effects on dynamics of functional network connectivity in patients treated for chronic suicidality.

The underlying brain mechanisms of ketamine in treating chronic suicidality and the characteristics of patients who will benefit from ketamine treatment remain unclear. To address these gaps, we investigated temporal variations of brain functional synchronisation in patients with suicidality treated with ketamine in a 6-week open-label oral ketamine trial. The trial's primary endpoint was the Beck Scale for Suicide Ideation (BSS). Patients who experienced greater than 50% improvement in BSS scores or had a BSS score less than 6 at the post-treatment and follow-up (10 weeks) visits were considered responders and persistent responders, respectively. The reoccurring and transient connectivity pattern (termed brain state) from 29 patients (45.6 years ± 14.5, 15 females) were investigated by dynamic functional connectivity analysis of resting-state functional MRI at the baseline, post-treatment, and follow-up. Post-treatment patients showed significantly more (FDR-Q = 0.03) transitions among whole brain states than at baseline. We also observed increased dwelling time (FDR-Q = 0.04) and frequency (FDR-Q = 0.04) of highly synchronised brain state at follow-up, which were significantly correlated with BSS scores (both FDR-Q = 0.008). At baseline, persistent responders had higher fractions (FDR-Q = 0.03, Cohen's d = 1.39) of a cognitive control network state with high connectivities than non-responders. These findings suggested that ketamine enhanced brain changes among different synchronisation patterns and enabled high synchronisation patterns in the long term, providing a possible biological pathway for its suicide-prevention effects. Moreover, differences in cognitive control states at baseline may be used for precise ketamine treatment planning.

Insights into the neurobiology of suicidality: explicating the role of glutamatergic systems through the lens of ketamine.

Suicidality is a prevalent mental health condition, and managing suicidal patients is one of the most challenging tasks for health care professionals due to the lack of rapid-acting, effective psychopharmacological treatment options. According to the literature, suicide has neurobiological underpinnings that are not fully understood, and current treatments for suicidal tendencies have considerable limitations. To treat suicidality and prevent suicide, new treatments are required; to achieve this, the neurobiological processes underlying suicidal behavior must be thoroughly investigated. Although multiple neurotransmitter systems, particularly serotonergic systems, have been studied in the past, less has been reported in relation to disruptions in glutamatergic neurotransmission, neuronal plasticity, and neurogenesis that result from stress-related abnormalities of the hypothalamic-pituitary-adrenal system. Informed by the literature, which reports robust antisuicidal and antidepressive properties of subanaesthetic doses of ketamine, this review aims to provide an examination of the neurobiology of suicidality (and relevant mood disorders) with implications of pertinent animal, clinical, and postmortem studies. We discuss dysfunctions in the glutamatergic system, which may play a role in the neuropathology of suicidality and the role of ketamine in restoring synaptic connectivity at the molecular levels.

Quantitative relations between BOLD responses, cortical energetics and impulse firing across cortical depth.

The blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal arises as a consequence of changes in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen ( CMR O 2 ) that in turn are modulated by changes in neural activity. Recent advances in imaging have achieved sub-millimetre resolution and allowed investigation of the BOLD response as a function of cortical depth. Here, we adapt our previous theory relating the BOLD signal to neural activity to produce a quantitative model that incorporates venous blood draining between cortical layers. The adjustable inputs to the model are the neural activity and a parameter governing this blood draining. A three-layer version for transient neural inputs and a multi-layer version for constant or tonic neural inputs are able to account for a variety of experimental results, including negative BOLD signals.

Microglial cell hyper-ramification and neuronal dendritic spine loss in the hippocampus and medial prefrontal cortex in a mouse model of PTSD.

Few animal models exist that successfully reproduce several core associative and non-associative behaviours relevant to post-traumatic stress disorder (PTSD), such as long-lasting fear reactions, hyperarousal, and subtle attentional and cognitive dysfunction. As such, these models may lack the face validity required to adequately model pathophysiological features of PTSD such as CNS grey matter loss and neuroinflammation. Here we aimed to investigate in a mouse model of PTSD whether contextual fear conditioning associated with a relatively high intensity footshock exposure induces loss of neuronal dendritic spines in various corticolimbic brain regions, as their regression may help explain grey matter reductions in PTSD patients. Further, we aimed to observe whether these changes were accompanied by alterations in microglial cell number and morphology, and increased expression of complement factors implicated in the mediation of microglial cell-mediated engulfment of dendritic spines. Adult male C57Bl6J mice were exposed to a single electric footshock and subsequently underwent phenotyping of various PTSD-relevant behaviours in the short (day 2-4) and longer-term (day 29-31). 32 days post-exposure the brains of these animals were subjected to Golgi staining of dendritic spines, microglial cell Iba-1 immunohistochemistry and immunofluorescent staining of the complement factors C1q and C4. Shock exposure promoted a lasting contextual fear response, decreased locomotor activity, exaggerated acoustic startle responses indicative of hyperarousal, and a short-term facilitation of sensorimotor gating function. The shock triggered loss of dendritic spines on pyramidal neurons was accompanied by increased microglial cell number and complexity in the medial prefrontal cortex and dorsal hippocampus, but not in the amygdala. Shock also increased expression of C1q in the pyramidal layer of the CA1 region of the hippocampus but not in other brain regions. The present study further elaborates on the face and construct validity of a mouse model of PTSD and provides a good foundation to explore potential molecular interactions between microglia and dendritic spines.

Cortical network models of impulse firing in the resting and active states predict cortical energetics.

Measurements of the cortical metabolic rate of glucose oxidation [CMR(glc(ox))] have provided a number of interesting and, in some cases, surprising observations. One is the decline in CMR(glc(ox)) during anesthesia and non-rapid eye movement (NREM) sleep, and another, the inverse relationship between the resting-state CMR(glc(ox)) and the transient following input from the thalamus. The recent establishment of a quantitative relationship between synaptic and action potential activity on the one hand and CMR(glc(ox)) on the other allows neural network models of such activity to probe for possible mechanistic explanations of these phenomena. We have carried out such investigations using cortical models consisting of networks of modules with excitatory and inhibitory neurons, each receiving excitatory inputs from outside the network in addition to intermodular connections. Modules may be taken as regions of cortical interest, the inputs from outside the network as arising from the thalamus, and the intermodular connections as long associational fibers. The model shows that the impulse frequency of different modules can differ from each other by less than 10%, consistent with the relatively uniform CMR(glc(ox)) observed across different regions of cortex. The model also shows that, if correlations of the average impulse rate between different modules decreases, there is a concomitant decrease in the average impulse rate in the modules, consistent with the observed drop in CMR(glc(ox)) in NREM sleep and under anesthesia. The model also explains why a transient thalamic input to sensory cortex gives rise to responses with amplitudes inversely dependent on the resting-state frequency, and therefore resting-state CMR(glc(ox)).

Utility of the cumulative stress and mismatch hypotheses in understanding the neurobiological impacts of childhood abuse and recent stress in youth with emerging mental disorder.

Childhood abuse has an enduring impact on the brain's stress system. Whether the effects of childhood abuse and adulthood stress are additive (cumulative stress hypothesis) or interactive (mismatch hypothesis) is widely disputed, however. The primary aim of this study was to test the utility of the cumulative stress and mismatch hypotheses in understanding brain and behaviour. We recruited 64 individuals (aged 14-26) from a specialised clinic for assessment and early intervention of mental health problems in young people. A T1-weighted MRI, a resting state fMRI and clinical assessment were acquired from each participant. Grey matter estimates and resting state functional connectivity (rsFC) of the hippocampus, amygdala and anterior cingulate cortex (ACC) were determined using segmentation and seed-to-voxel rsFC analyses. We explored the effects of childhood abuse and recent stress on the structure and function of the regions of interest within general linear models. Worse psychiatric symptoms were significantly related to higher levels of life time stress. Individuals with mismatched childhood and recent stress levels had reduced left hippocampal volume, reduced ACC-ventrolateral prefrontal cortex rsFC and greater ACC-hippocampus rsFC, compared to individuals with matched childhood and recent stress levels. These results show specific utility of the cumulative stress hypothesis in understanding psychiatric symptomatology and of the mismatch hypothesis in modelling hippocampal grey matter, prefrontal rsFC, and prefrontal-hippocampal rsFC. We provide novel evidence for the enduring impact of childhood abuse on stress reactivity in a clinical population, and demonstrate the distinct effects of stress in different systems. Hum Brain Mapp 38:2709-2721, 2017. © 2017 Wiley Periodicals, Inc.

Cortical energy demands of signaling and nonsignaling components in brain are conserved across mammalian species and activity levels.

The continuous need for ion gradient restoration across the cell membrane, a prerequisite for synaptic transmission and conduction, is believed to be a major factor for brain's high oxidative demand. However, do energy requirements of signaling and nonsignaling components of cortical neurons and astrocytes vary with activity levels and across species? We derived oxidative ATP demand associated with signaling (P(s)) and nonsignaling (P(ns)) components in the cerebral cortex using species-specific physiologic and anatomic data. In rat, we calculated glucose oxidation rates from layer-specific neuronal activity measured across different states, spanning from isoelectricity to awake and sensory stimulation. We then compared these calculated glucose oxidation rates with measured glucose metabolic data for the same states as reported by 2-deoxy-glucose autoradiography. Fixed values for P(s) and P(ns) were able to predict the entire range of states in the rat. We then calculated glucose oxidation rates from human EEG data acquired under various conditions using fixed P(s) and P(ns) values derived for the rat. These calculated metabolic data in human cerebral cortex compared well with glucose metabolism measured by PET. Independent of species, linear relationship was established between neuronal activity and neuronal oxidative demand beyond isoelectricity. Cortical signaling requirements dominated energy demand in the awake state, whereas nonsignaling requirements were ∼20% of awake value. These predictions are supported by (13)C magnetic resonance spectroscopy results. We conclude that mitochondrial energy support for signaling and nonsignaling components in cerebral cortex are conserved across activity levels in mammalian species.

White matter tractography in early psychosis: clinical and neurocognitive associations.

BACKGROUND: While many diffusion tensor imaging (DTI) investigations have noted disruptions to white matter integrity in individuals with chronic psychotic disorders, fewer studies have been conducted in young people at the early stages of disease onset. Using whole tract reconstruction techniques, the aim of this study was to identify the white matter pathology associated with the common clinical symptoms and executive function impairments observed in young people with psychosis. METHODS: We obtained MRI scans from young people with psychosis and healthy controls. Eighteen major white matter tracts were reconstructed to determine group differences in fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) and then were subsequently correlated with symptomatology and neurocognitive performance. RESULTS: Our study included 42 young people with psychosis (mean age 23 yr) and 45 healthy controls (mean age 25 yr). Compared with the control group, the psychosis group had reduced FA and AD in the left inferior longitudinal fasciculus (ILF) and forceps major indicative of axonal disorganization, reduction and/or loss. These changes were associated with worse overall psychiatric symptom severity, increases in positive and negative symptoms, and worse current levels of depression. The psychosis group also showed FA reductions in the left superior longitudinal fasciculus that were associated with impaired neurocognitive performance in attention and semantic fluency. LIMITATIONS: Our analysis grouped 4 subcategories of psychosis together, and a larger follow-up study comparing affective and nonaffective psychoses is warranted. CONCLUSION: Our findings suggest that impaired axonal coherence in the left ILF and forceps major underpin psychiatric symptoms in young people in the early stages of psychosis.

img2fmri: a python package for predicting group-level fMRI responses to visual stimuli using deep neural networks.

Here we introduce a new python package, img2fmri, to predict group-level fMRI responses to individual images. This prediction model uses an artificial deep neural network (DNN), as DNNs have been successful at predicting cortical responses in the human visual cortex when trained on real world visual categorization tasks. To validate our model, we predict fMRI responses to images our model has not previously seen from a new dataset. We then show how our frame-by-frame prediction model can be extended to a continuous visual stimulus by predicting an fMRI response to Pixar Animation Studio's short film Partly Cloudy. In analyzing the timepoint-timepoint similarity of our predicted fMRI response around human-annotated event boundaries in the movie, we find that our model outperforms the baseline model in describing the dynamics of the real fMRI response around these event boundaries, particularly in the timepoints just before and at an event. These analyses suggest that in visual areas of the brain, at least some of the temporal dynamics we see in the brain's processing of continuous, naturalistic stimuli can be explained by dynamics in the stimulus itself, since they can be predicted from our frame-by-frame model. All code, analyses, tutorials, and installation instructions can be found at https://github.com/dpmlab/img2fmri.

Ketamine and Zinc: Treatment of Anorexia Nervosa Via Dual NMDA Receptor Modulation.

Anorexia nervosa is a disorder associated with serious adverse health outcomes, for which there is currently considerable treatment ineffectiveness. Characterised by restrictive eating behaviours, distorted body image perceptions and excessive physical activity, there is growing recognition anorexia nervosa is associated with underlying dysfunction in excitatory and inhibitory neurometabolite metabolism and signalling. This narrative review critically explores the role of N-methyl-D-aspartate receptor-mediated excitatory and inhibitory neurometabolite dysfunction in anorexia nervosa and its associated biomarkers. The existing magnetic resonance spectroscopy literature in anorexia nervosa is reviewed and we outline the brain region-specific neurometabolite changes that have been reported and their connection to anorexia nervosa psychopathology. Considering the proposed role of dysfunctional neurotransmission in anorexia nervosa, the potential utility of zinc supplementation and sub-anaesthetic doses of ketamine in normalising this is discussed with reference to previous research in anorexia nervosa and other neuropsychiatric conditions. The rationale for future research to investigate the combined use of low-dose ketamine and zinc supplementation to potentially extend the therapeutic benefits in anorexia nervosa is subsequently explored and promising biological markers for assessing and potentially predicting treatment response are outlined.

Electrophysiological phenotypes of suicidality predict prolonged response to oral ketamine treatment.

Oral ketamine has shown to be a rapid-acting antidepressant and a potential treatment option for suicidality, however, repeated doses are often required. Objective markers of prolonged treatment response are needed to help individuals and clinicians make informed treatment decisions. This secondary analysis sought to identify objective electrophysiological predictors of both prolonged response and dose sensitivity to low-dose oral ketamine in people with chronic suicidality. Individuals with a Beck Scale for Suicide Ideation total score (BSS) ≥ 6 (N = 29) completed a six-week ketamine treatment, pre-treatment electroencephalography and follow-up assessment of suicidality (four weeks from the final ketamine dose). Prolonged response was observed in 52% of participants (follow-up BSS reduced by 50% or ≤6); nearly half were prolonged non-responders. There was decisive evidence for a predictive Bayesian linear regression model with follow-up BSS score as the response variable and pre-treatment auditory evoked power bands as predictors (theta, alpha and beta frequencies, BF10 = 17,948, R2 = 0.70). A Bayesian one-way ANOVA indicated strong evidence for a model of positive association between auditory evoked power and ketamine dose sensitivity (theta-alpha BF+0 = 108, effect size δ = 1.3, 95% CI 0.5-2.1; high-beta BF+0 = 7.4, δ = 0.8, 95% CI 0.1-1.6). Given auditory evoked power may index serotonin neurotransmission, these results suggest that a prolonged response to ketamine may, in part, be mediated by pre-treatment serotonergic functioning. In addition, the observed beta power differences may arise from GABAergic functioning. These suicidality phenotypes, identifiable by pre-treatment electrophysiology, may aid diagnosis, treatment selection and prediction of prolonged treatment outcome.

Correlating anterior insula gray matter volume changes in young people with clinical and neurocognitive outcomes: an MRI study.

BACKGROUND: The anterior insula cortex is considered to be both the structural and functional link between experience, affect, and behaviour. Magnetic resonance imaging (MRI) studies have shown changes in anterior insula gray matter volume (GMV) in psychosis, bipolar, depression and anxiety disorders in older patients, but few studies have investigated insula GMV changes in young people. This study examined the relationship between anterior insula GMV, clinical symptom severity and neuropsychological performance in a heterogeneous cohort of young people presenting for mental health care. METHODS: Participants with a primary diagnosis of depression (n = 43), bipolar disorder (n = 38), psychosis (n = 32), anxiety disorder (n = 12) or healthy controls (n = 39) underwent structural MRI scanning, and volumetric segmentation of the bilateral anterior insula cortex was performed using the FreeSurfer application. Statistical analysis examined the linear and quadratic correlations between anterior insula GMV and participants' performance in a battery of clinical and neuropsychological assessments. RESULTS: Compared to healthy participants, patients had significantly reduced GMV in the left anterior insula (t = 2.05, p = .042) which correlated with reduced performance on a neuropsychological task of attentional set-shifting (ρ = .32, p = .016). Changes in right anterior insula GMV was correlated with increased symptom severity (r = .29, p = .006) and more positive symptoms (r = .32, p = .002). CONCLUSIONS: By using the novel approach of examining a heterogeneous cohort of young depression, anxiety, bipolar and psychosis patients together, this study has demonstrated that insula GMV changes are associated with neurocognitive deficits and clinical symptoms in such young patients.

Six-week oral ketamine treatment for chronic suicidality is associated with increased grey matter volume.

Chronic suicidality has been associated with neuronal atrophy in cortico-striato-limbic regions and is thought to be mediated via a glutamatergic imbalance. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been posited to exert anti-suicidal effects by promoting neurogenesis via modulation of glutamatergic transmission. This voxel-based morphometry study examined the effect of ketamine on whole brain grey matter in adults with chronic suicidality. Grey matter in the periaqueductal grey, nucleus accumbens, putamen, caudate, and thalamus was significantly increased following 6 weeks of low dose oral ketamine treatment. These results support the notion that ketamine rapidly enhances synaptic plasticity within striato-limbic regions.

Synapse regression in depression: the role of 5-HT receptors in modulating NMDA receptor function and synaptic plasticity.

Depression is accompanied by an increase in activity in the amygdala and a decrease in the rostral anterior cingulate cortex (rACC), with the former attributed to a failure of the latter to exert its normal inhibitory influence. This failure is likely due to regression of synaptic connections between the rACC and the amygdala, a process reversed in part by selective serotonin reuptake inhibitors (SSRIs). The present work presents a hypothesis as to how SSRIs might bring about this process and hence normalization of activity, at least in patients that are responsive to SSRIs. Serotonin receptors of the excitatory 5-HT(2A)R class increase N-methyl-D-aspartate receptor (NMDAR) efficacy, while those of the inhibitory 5-HT(1A)R class decrease NMDAR efficacy. A decrease of 5-HT transporter (5-HTT) efficacy, either during human development through functional polymorphisms, or in animals through 5-HTT transgenic knockouts, is accompanied by a decrease in 5-HT(1A)R and hence an increase in excitability and NMDAR efficacy which drives an increase in synaptic spines in the amygdala. As the limbic region of the brain normally possesses high levels of 5-HT(1A)R the effect of loss of these is to increase excitation in this region, as is observed. Changes in the level of extracellular 5-HT in adult animals also modulates the density of synaptic spines, with these increasing with an increase in 5-HT, possibly as a consequence of increases in 5-HT(2A)R activity over that of 5-HT(1A)R. Increasing extracellular levels of 5-HT with SSRIs would then lead to an increase in excitability and in synaptic spines for afferents in the dorsal rostral anterior cingulate cortex but not in the ventral regions such as the amygdala that have few 5-HT(2A)R. This allows dorsal regions to once more exert their inhibitory influence over ventral regions. In this way, SSRIs may exert their effect in normalizing dorsal hypometabolism and ventral hypermetabolism in those suffering from depression.

P2X7 receptor knockout mice display less aggressive biting behaviour correlating with increased brain activation in the piriform cortex.

P2X7 receptors are implicated in the pathophysiology of psychiatric conditions such as depression and bipolar disorder. P2X7 receptors regulate the release of pro-inflammatory cytokines from microglia, and gain-of-function P2X7 mutations may contribute to the neuroinflammation found in affective disorders. However, the role of this receptor in mediating other mental health conditions and aberrant behaviours requires further examination. The current study we investigated the effects of germline genetic deletion of P2xr7 on social and marble burying behaviours in mice throughout the critical adolescent developmental period. Marble burying behaviour is thought to provide a mouse model of obsessive-compulsive disorder (OCD). We also characterised the effects of P2rx7 deletion on aggressive attack behaviour in adult mice and subsequently quantifieded microglial cell densities and c-Fos expression, a marker of neuronal activation. P2rx7 knockout mice displayed reduced OCD-related marble burying behaviour which was most pronounced in late adolescence/early adulthood. P2rx7 knockout mice also exhibited reduced aggressive attack behaviours in adulthood in the resident-intruder test. Reduced aggression in P2xr7 knockout mice did not coincide with changes to microglial cell densities, however c-Fos expression was elevated in the piriform cortex of P2rx7 knockout mice compared to wildtype mice. This study suggests that the P2X7 receptor might serve as a novel target for serenic or anti-OCD therapeutics.

Distribution of glutamate transporter GLAST in membranes of cultured astrocytes in the presence of glutamate transport substrates and ATP.

Neurotransmitter L-glutamate released at central synapses is taken up and "recycled" by astrocytes using glutamate transporter molecules such as GLAST and GLT. Glutamate transport is essential for prevention of glutamate neurotoxicity, it is a key regulator of neurotransmitter metabolism and may contribute to mechanisms through which neurons and glia communicate with each other. Using immunocytochemistry and image analysis we have found that extracellular D-aspartate (a typical substrate for glutamate transport) can cause redistribution of GLAST from cytoplasm to the cell membrane. The process appears to involve phosphorylation/dephosphorylation and requires intact cytoskeleton. Glutamate transport ligands L-trans-pyrrolidine-2,4-dicarboxylate and DL-threo-3-benzyloxyaspartate but not anti,endo-3,4-methanopyrrolidine dicarboxylate have produced similar redistribution of GLAST. Several representative ligands for glutamate receptors whether of ionotropic or metabotropic type, were found to have no effect. In addition, extracellular ATP induced formation of GLAST clusters in the cell membranes by a process apparently mediated by P2 receptors. The present data suggest that GLAST can rapidly and specifically respond to changes in the cellular environment thus potentially helping to fine-tune the functions of astrocytes.

Rottlerin inhibits (Na+, K+)-ATPase activity in brain tissue and alters D-aspartate dependent redistribution of glutamate transporter GLAST in cultured astrocytes.

The naturally occurring toxin rottlerin has been used by other laboratories as a specific inhibitor of protein kinase C-delta (PKC-delta) to obtain evidence that the activity-dependent distribution of glutamate transporter GLAST is regulated by PKC-delta mediated phosphorylation. Using immunofluorescence labelling for GLAST and deconvolution microscopy we have observed that D-aspartate-induced redistribution of GLAST towards the plasma membranes of cultured astrocytes was abolished by rottlerin. In brain tissue in vitro, rottlerin reduced apparent activity of (Na+, K+)-dependent ATPase (Na+, K+-ATPase) and increased oxygen consumption in accordance with its known activity as an uncoupler of oxidative phosphorylation ("metabolic poison"). Rottlerin also inhibited Na+, K+-ATPase in cultured astrocytes. As the glutamate transport critically depends on energy metabolism and on the activity of Na+, K+-ATPase in particular, we suggest that the metabolic toxicity of rottlerin and/or the decreased activity of the Na+, K+-ATPase could explain both the glutamate transport inhibition and altered GLAST distribution caused by rottlerin even without any involvement of PKC-delta-catalysed phosphorylation in the process.

Purinergic P2X(7) receptor antagonists: Chemistry and fundamentals of biological screening.

The purinergic P2X(7) receptor is a unique member of the ATP-gated P2X family. This receptor has been implicated in numerous diseases and many structurally diverse ligands have been discovered via high throughput screening. This perspective will attempt to highlight some of the most recent key findings in both the biology and chemistry.

Positive and negative symptoms in schizophrenia: the NMDA receptor hypofunction hypothesis, neuregulin/ErbB4 and synapse regression.

Carlsson has put forward the hypothesis that the positive and negative symptoms of schizophrenia are due to failure of mesolimbic and mesocortical projections consequent on hypofunction of the glutamate N-methyl-d-aspartate (NMDA) receptor. The hypothesis has been recently emphasized in this Journal that the loss of synaptic spines with NMDA receptors, which can be precipitated by stress, can explain the emergence of positive symptoms such as hallucinations and that this synapse regression involves molecules such as neuregulin and its receptor ErbB4 that have been implicated in schizophrenia. In this essay these two hypotheses are brought together in a single scheme in which emphasis is placed on the molecular pathways from neuregulin/ErbB4, to modulation of the NMDA receptors, subsequent changes in the synaptic spine's cytoskeletal apparatus and so regression of the spines. It is suggested that identification of the molecular constituents of this pathway will allow synthesis of suitable substances for removing the hypofunction of NMDA receptors and so the phenotypic consequences that flow from this hypofunction.

A model of amygdala function following plastic changes at specific synapses during extinction.

The synaptic networks in the amygdala have been the subject of intense interest in recent times, primarily because of the role of this structure in emotion. Fear and its extinction depend on the workings of these networks, with particular interest in extinction because of its potential to ameliorate adverse symptoms associated with post-traumatic stress disorder. Here we place emphasis on the extinction networks revealed by recent techniques, and on the probable plasticity properties of their synaptic connections. We use modules of neurons representing each of the principal components identified as involved in extinction. Each of these modules consists of neural networks, containing specific ratios of excitatory and specialized inhibitory neurons as well as synaptic plasticity mechanisms appropriate for the component of the amygdala they represent. While these models can produce dynamic output, here we concentrate on the equilibrium outputs and do not model the details of the plasticity mechanisms. Pavlovian fear conditioning generates a fear memory in the lateral amygdala module that leads to activation of neurons in the basal nucleus fear module but not in the basal nucleus extinction module. Extinction protocols excite infralimbic medial prefrontal cortex neurons (IL) which in turn excite so-called extinction neurons in the amygdala, leading to the release of endocannabinoids from them and an increase in efficacy of synapses formed by lateral amygdala neurons on them. The model simulations show how such a mechanism could explain experimental observations involving the role of IL as well as endocannabinoids in different temporal phases of extinction.