Topic: Impairments

Organization of thalamic networks and mechanisms of dysfunction in schizophrenia and autism

Thalamic networks, at the core of thalamocortical and thalamosubcortical communications, underlie processes of perception, attention, memory, emotions, and the sleep-wake cycle, and are disrupted in mental disorders, including schizophrenia and autism. However, the underlying mechanisms of pathology are unknown. I will present novel evidence on key organizational principles, structural, and molecular features of thalamocortical networks, as well as critical thalamic pathway interactions that are likely affected in disorders. This data can facilitate modeling typical and abnormal brain function and can provide the foundation to understand heterogeneous disruption of these networks in sleep disorders, attention deficits, and cognitive and affective impairments in schizophrenia and autism, with important implications for the design of targeted therapeutic interventions

Neural mechanisms governing the learning and execution of avoidance behavior

The nervous system orchestrates adaptive behaviors by intricately coordinating responses to internal cues and environmental stimuli. This involves integrating sensory input, managing competing motivational states, and drawing on past experiences to anticipate future outcomes. While traditional models attribute this complexity to interactions between the mesocorticolimbic system and hypothalamic centers, the specific nodes of integration have remained elusive. Recent research, including our own, sheds light on the midline thalamus's overlooked role in this process. We propose that the midline thalamus integrates internal states with memory and emotional signals to guide adaptive behaviors. Our investigations into midline thalamic neuronal circuits have provided crucial insights into the neural mechanisms behind flexibility and adaptability. Understanding these processes is essential for deciphering human behavior and conditions marked by impaired motivation and emotional processing. Our research aims to contribute to this understanding, paving the way for targeted interventions and therapies to address such impairments.

Exploring Lifespan Memory Development and Intervention Strategies for Memory Decline through a Unified Model-Based Assessment

Understanding and potentially reversing memory decline necessitates a comprehensive examination of memory's evolution throughout life. Traditional memory assessments, however, suffer from a lack of comparability across different age groups due to the diverse nature of the tests employed. Addressing this gap, our study introduces a novel, ACT-R model-based memory assessment designed to provide a consistent metric for evaluating memory function across a lifespan, from 5 to 85-year-olds. This approach allows for direct comparison across various tasks and materials tailored to specific age groups. Our findings reveal a pronounced U-shaped trajectory of long-term memory function, with performance at age 5 mirroring those observed in elderly individuals with impairments, highlighting critical periods of memory development and decline. Leveraging this unified assessment method, we further investigate the therapeutic potential of rs-fMRI-guided TBS targeting area 8AV in individuals with early-onset Alzheimer’s Disease—a region implicated in memory deterioration and mood disturbances in this population. This research not only advances our understanding of memory's lifespan dynamics but also opens new avenues for targeted interventions in Alzheimer’s Disease, marking a significant step forward in the quest to mitigate memory decay.

Investigating face processing impairments in Developmental Prosopagnosia: Insights from behavioural tasks and lived experience

The defining characteristic of development prosopagnosia is severe difficulty recognising familiar faces in everyday life. Numerous studies have reported that the condition is highly heterogeneous in terms of both presentation and severity with many mixed findings in the literature. I will present behavioural data from a large face processing test battery (n = 24 DPs) as well as some early findings from a larger survey of the lived experience of individuals with DP and discuss how insights from individuals' real-world experience can help to understand and interpret lab-based data.

Establishment and aging of the neuronal DNA methylation landscape in the hippocampus

The hippocampus is a brain region with key roles in memory formation, cognitive flexibility and emotional control. Yet hippocampal function is impaired severely during aging and in neurodegenerative diseases, and impairments in hippocampal function underlie age-related cognitive decline. Accumulating evidence suggests that the deterioration of the neuron-specific epigenetic landscape during aging contributes to their progressive, age-related dysfunction. For instance, we have recently shown that aging is associated with pronounced alterations of neuronal DNA methylation patterns in the hippocampus. Because neurons are generated mostly during development with limited replacement in the adult brain, they are particularly long-lived cells and have to maintain their cell-type specific gene expression programs life-long in order to preserve brain function. Understanding the epigenetic mechanisms that underlie the establishment and long-term maintenance of neuron-specific gene expression programs, will help us to comprehend the sources and consequences of their age-related deterioration. In this talk, I will present our recent work that investigated the role of DNA methylation in the establishment of neuronal gene expression programs and neuronal function, using adult neurogenesis in the hippocampus as a model. I will then describe the effects of aging on the DNA methylation landscape in the hippocampus and discuss the malleability of the aging neuronal methylome to lifestyle and environmental stimulation.

Investigating semantics above and beyond language: a clinical and cognitive neuroscience approach

The ability to build, store, and manipulate semantic representations lies at the core of all our (inter)actions. Combining evidence from cognitive neuroimaging and experimental neuropsychology, I study the neurocognitive correlates of semantic knowledge in relation to other cognitive functions, chiefly language. In this talk, I will start by reviewing neuroimaging findings supporting the idea that semantic representations are encoded in distributed yet specialized cortical areas (1), and rapidly recovered (2) according to the requirement of the task at hand (3). I will then focus on studies conducted in neurodegenerative patients, offering a unique window on the key role played by a structurally and functionally heterogeneous piece of cortex: the anterior temporal lobe (4,5). I will present pathological, neuroimaging, cognitive, and behavioral data illustrating how damages to language-related networks can affect or spare semantic knowledge as well as possible paths to functional compensation (6,7). Time permitting, we will discuss the neurocognitive dissociation between nouns and verbs (8) and how verb production is differentially impacted by specific language impairments (9).

Targeting thalamic circuits rescues motor and mood deficits in PD mice

Although bradykinesia, tremor, and rigidity are hallmark motor defects in Parkinson’s disease (PD) patients, they also experience motor learning impairments and non-motor symptoms such as depression. The neural basis for these different PD symptoms are not well understood. While current treatments are effective for locomotion deficits in PD, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking. We found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN), and nucleus accumbens (NAc). While PF-->CPu and PF-->STN circuits are critical for locomotion and motor learning respectively, inhibition of the PF-->NAc circuit induced a depression-like state. While chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation at PF-->STN synapses restored motor learning behavior in PD model mice. Furthermore, activation of NAc-projecting PF neurons rescued depression-like PD phenotypes. Importantly, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.

What's wrong with the prosopagnosia literature? A new approach to diagnosing and researching the condition

Developmental prosopagnosia is characterised by severe, lifelong difficulties when recognising facial identity. Most researchers require prosopagnosia cases exhibit ultra-conservative levels of impairment on the Cambridge Face Memory Test before they include them in their experiments. This results in the majority of people who believe that they have this condition being excluded from the scientific literature. In this talk I outline the many issues that will afflict prosopagnosia research if this continues, and show that these excluded cases do exhibit impairments on all commonly used diagnostic tests when a group-based method of assessment is utilised. I propose a paradigm shift away from cognitive task-based approaches to diagnosing prosopagnosia, and outline a new way that researchers can investigate this condition.

Extrinsic control and intrinsic computation in the hippocampal CA1 network

A key issue in understanding circuit operations is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. Several studies have lesioned or silenced inputs to area CA1 of the hippocampus - either area CA3 or the entorhinal cortex and examined the effect on CA1 pyramidal cells. However, the types of the reported physiological impairments vary widely, primarily because simultaneous manipulations of these redundant inputs have never been performed. In this study, I combined optogenetic silencing of unilateral and bilateral mEC, of the local CA1 region, and performed bilateral pharmacogenetic silencing of CA3. I combined this with high spatial resolution extracellular recordings along the CA1-dentate axis. Silencing the medial entorhinal largely abolished extracellular theta and gamma currents in CA1, without affecting firing rates. In contrast, CA3 and local CA1 silencing strongly decreased firing of CA1 neurons without affecting theta currents. Each perturbation reconfigured the CA1 spatial map. Yet, the ability of the CA1 circuit to support place field activity persisted, maintaining the same fraction of spatially tuned place fields. In contrast to these results, unilateral mEC manipulations that were ineffective in impacting place cells during awake behavior were found to alter sharp-wave ripple sequences activated during sleep. Thus, intrinsic excitatory-inhibitory circuits within CA1 can generate neuronal assemblies in the absence of external inputs, although external synaptic inputs are critical to reconfigure (remap) neuronal assemblies in a brain-state dependent manner.

Can I be bothered? Neural and computational mechanisms underlying the dynamics of effort processing (BACN Early-career Prize Lecture 2021)

From a workout at the gym to helping a colleague with their work, everyday we make decisions about whether we are willing to exert effort to obtain some sort of benefit. Increases in how effortful actions and cognitive processes are perceived to be has been linked to clinically severe impairments to motivation, such as apathy and fatigue, across many neurological and psychiatric conditions. However, the vast majority of neuroscience research has focused on understanding the benefits for acting, the rewards, and not on the effort required. As a result, the computational and neural mechanisms underlying how effort is processed are poorly understood. How do we compute how effortful we perceive a task to be? How does this feed into our motivation and decisions of whether to act? How are such computations implemented in the brain? and how do they change in different environments? I will present a series of studies examining these questions using novel behavioural tasks, computational modelling, fMRI, pharmacological manipulations, and testing in a range of different populations. These studies highlight how the brain represents the costs of exerting effort, and the dynamic processes underlying how our sensitivity to effort changes as a function of our goals, traits, and socio-cognitive processes. This work provides new computational frameworks for understanding and examining impaired motivation across psychiatric and neurological conditions, as well as why all of us, sometimes, can’t be bothered.

Western diet consumption and memory impairment: what, when, and how?

Habitual consumption of a “Western diet”, containing higher than recommended levels of simple sugars and saturated fatty acids, is associated with cognitive impairments in humans and in various experimental animal models. Emerging findings reveal that the specific mnemonic processes that are disrupted by Western diet consumption are those that rely on the hippocampus, a brain region classically linked with memory control and more recently with the higher-order control of food intake. Our laboratory has established rat models in which excessive consumption of different components of a Western diet during the juvenile and adolescent periods of development yields long-term impairments in hippocampal-dependent memory function without concomitant increases in total caloric intake, body weight, or adiposity. Our ongoing work is investigating alterations in the gut microbiome as a potential underlying neurobiological mechanism linking early life unhealthy dietary factors to adverse neurocognitive outcomes.

The Synaptome Architecture of the Brain: Lifespan, disease, evolution and behavior

The overall aim of my research is to understand how the organisation of the synapse, with particular reference to the postsynaptic proteome (PSP) of excitatory synapses in the brain, informs the fundamental mechanisms of learning, memory and behaviour and how these mechanisms go awry in neurological dysfunction. The PSP indeed bears a remarkable burden of disease, with components being disrupted in disorders (synaptopathies) including schizophrenia, depression, autism and intellectual disability. Our work has been fundamental in revealing and then characterising the unprecedented complexity (>1000 highly conserved proteins) of the PSP in terms of the subsynaptic architecture of postsynaptic proteins such as PSD95 and how these proteins assemble into complexes and supercomplexes in different neurons and regions of the brain. Characterising the PSPs in multiple species, including human and mouse, has revealed differences in key sets of functionally important proteins, correlates with brain imaging and connectome data, and a differential distribution of disease-relevant proteins and pathways. Such studies have also provided important insight into synapse evolution, establishing that vertebrate behavioural complexity is a product of the evolutionary expansion in synapse proteomes that occurred ~500 million years ago. My lab has identified many mutations causing cognitive impairments in mice before they were found to cause human disorders. Our proteomic studies revealed that >130 brain diseases are caused by mutations affecting postsynaptic proteins. We uncovered mechanisms that explain the polygenic basis and age of onset of schizophrenia, with postsynaptic proteins, including PSD95 supercomplexes, carrying much of the polygenic burden. We discovered the “Genetic Lifespan Calendar”, a genomic programme controlling when genes are regulated. We showed that this could explain how schizophrenia susceptibility genes are timed to exert their effects in young adults. The Genes to Cognition programme is the largest genetic study so far undertaken into the synaptic molecular mechanisms underlying behaviour and physiology. We made important conceptual advances that inform how the repertoire of both innate and learned behaviours is built from unique combinations of postsynaptic proteins that either amplify or attenuate the behavioural response. This constitutes a key advance in understanding how the brain decodes information inherent in patterns of nerve impulses, and provides insight into why the PSP has evolved to be so complex, and consequently why the phenotypes of synaptopathies are so diverse. Our most recent work has opened a new phase, and scale, in understanding synapses with the first synaptome maps of the brain. We have developed next-generation methods (SYNMAP) that enable single-synapse resolution molecular mapping across the whole mouse brain and extensive regions of the human brain, revealing the molecular and morphological features of a billion synapses. This has already uncovered unprecedented spatiotemporal synapse diversity organised into an architecture that correlates with the structural and functional connectomes, and shown how mutations that cause cognitive disorders reorganise these synaptome maps; for example, by detecting vulnerable synapse subtypes and synapse loss in Alzheimer’s disease. This innovative synaptome mapping technology has huge potential to help characterise how the brain changes during normal development, including in specific cell types, and with degeneration, facilitating novel pathways to diagnosis and therapy.

Extrinsic control and autonomous computation in the hippocampal CA1 circuit

In understanding circuit operations, a key issue is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. Because pyramidal cells in CA1 do not have local recurrent projections, it is currently assumed that firing in CA1 is inherited from its inputs – thus, entorhinal inputs provide communication with the rest of the neocortex and the outside world, whereas CA3 inputs provide internal and past memory representations. Several studies have attempted to prove this hypothesis, by lesioning or silencing either area CA3 or the entorhinal cortex and examining the effect of firing on CA1 pyramidal cells. Despite the intense and careful work in this research area, the magnitudes and types of the reported physiological impairments vary widely across experiments. At least part of the existing variability and conflicts is due to the different behavioral paradigms, designs and evaluation methods used by different investigators. Simultaneous manipulations in the same animal or even separate manipulations of the different inputs to the hippocampal circuits in the same experiment are rare. To address these issues, I used optogenetic silencing of unilateral and bilateral mEC, of the local CA1 region, and performed bilateral pharmacogenetic silencing of the entire CA3 region. I combined this with high spatial resolution recording of local field potentials (LFP) in the CA1-dentate axis and simultaneously collected firing pattern data from thousands of single neurons. Each experimental animal had up to two of these manipulations being performed simultaneously. Silencing the medial entorhinal (mEC) largely abolished extracellular theta and gamma currents in CA1, without affecting firing rates. In contrast, CA3 and local CA1 silencing strongly decreased firing of CA1 neurons without affecting theta currents. Each perturbation reconfigured the CA1 spatial map. Yet, the ability of the CA1 circuit to support place field activity persisted, maintaining the same fraction of spatially tuned place fields, and reliable assembly expression as in the intact mouse. Thus, the CA1 network can maintain autonomous computation to support coordinated place cell assemblies without reliance on its inputs, yet these inputs can effectively reconfigure and assist in maintaining stability of the CA1 map.

Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease

Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD+) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). Here, we analysed the metabolomic changes in flies over-expressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD+ protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD+ or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer’s disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer’s disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B, are associated with a decrease in the risk and severity of Alzheimer’s disease. We suggest that enhancing the availability of NAD+ by either vitamin B supplements or the inhibition of NAD+-dependent enzymes, such as PARPs are potential therapies for Alzheimer’s disease.

Neural impairments in Fragile X Syndrome

Analogical reasoning and metaphor processing in autism - Similarities & differences

In this talk, I will present the results of two recent systematic reviews and meta-analyses related to analogical reasoning and metaphor processing in autism, together with the results of a study that investigated verbal analogical reasoning and metaphor processing in the same sample of participants. Both metaphors and analogies rely on exploiting similarities, and they necessitate contextual processing. Nevertheless, our findings relating to metaphor processing and analogical reasoning showed distinct patterns. Whereas analogical reasoning emerged as a relative strength in autism, metaphor processing was found to be a relative weakness. Additionally, both meta-analytic studies investigated the relations between the level of intelligence of participants included in the studies, and the effect size of group differences between the autistic and typically developing (TD) samples. These analyses suggested in the case of analogical reasoning that the relative advantage of ASD participants might only be present in the case of individuals with lower levels of intelligence. By contrast, impairments in metaphor processing appeared to be more pronounced in the case of individuals with relatively lower levels of (verbal) intelligence. In our experimental study, we administered both verbal analogies and metaphors to the same sample of high-functioning autistic participants and TD controls. The two groups were matched on age, verbal IQ, working memory and educational background. Our aim was to understand better the similarities and differences between processing analogies and metaphors, and to see whether the advantage in analogical reasoning and disadvantage in metaphor processing is universal in autism.

Firing Homeostasis in Neural Circuits: From Basic Principles to Malfunctions

Neural circuit functions are stabilized by homeostatic mechanisms at long timescales in response to changes in experience and learning. However, we still do not know which specific physiological variables are being stabilized, nor which cellular or neural-network components comprise the homeostatic machinery. At this point, most evidence suggests that the distribution of firing rates amongst neurons in a brain circuit is the key variable that is maintained around a circuit-specific set-point value in a process called firing rate homeostasis. Here, I will discuss our recent findings that implicate mitochondria as a central player in mediating firing rate homeostasis and its impairments. While mitochondria are known to regulate neuronal variables such as synaptic vesicle release or intracellular calcium concentration, we searched for the mitochondrial signaling pathways that are essential for homeostatic regulation of firing rates. We utilize basic concepts of control theory to build a framework for classifying possible components of the homeostatic machinery in neural networks. This framework may facilitate the identification of new homeostatic pathways whose malfunctions drive instability of neural circuits in distinct brain disorders.

Toward an understanding of the impact of prenatal exposure to environmental contaminants on brain development

The risks of in utero and early exposure to environmental contaminants, such as heavy metals and persistent organic pollutants, on child neurodevelopment is now established, however our understanding of how these contaminants alter the human brain is very limited. To address this issue, more effort must be made to integrate brain imaging tools with epidemiological studies. In this seminar, I will be presenting EEG and MRI data collected in birth-cohort studies where impairments of cognitive and sensory functions were observed in association with prenatal exposure to mercury, lead, PCB or organophosphate insecticides. Results obtained in children and adolescents suggest that each pollutant might affect different levels of brain processing and that frontal regions are particularly vulnerable.

Role of Oxytocin in regulating microglia functions to prevent brain damage of the developing brain

Every year, 30 million infants worldwide are delivered after intra-uterine growth restriction (IUGR) and 15 million are born preterm. These two conditions are the leading causes of ante/perinatal stress and brain injury responsible for neurocognitive and behavioral disorders in more than 9 million children each year. Both prematurity and IUGR are associated with perinatal systemic inflammation, a key factor associated with neuroinflammation and identified to be the best predictor of subsequent neurological impairments. Most of pharmacological candidates have failed to demonstrate any beneficial effect to prevent perinatal brain damage. In contrast, environmental enrichment based on developmental care, skin-to-skin contact and vocal/music intervention appears to confer positive effects on brain structure and function. However, mechanisms underlying these effects remain unknown. There is strong evidence that an adverse environment during pregnancy and the perinatal period can influence hormonal responses of the newborn with long-lasting neurobehavioral consequences in infancy and adulthood. Excessive cortisol release in response to perinatal stress induces pro-inflammatory and brain-programming effects. These deleterious effects are known to be balanced by Oxytocin (OT), a neuropeptide playing a key role during the perinatal period and parturition, in social behavior and regulating the central inflammatory response to injury in the adult brain. Using a rodent model of IUGR associated with perinatal brain damage, we recently reported that Carbetocin, a brain permeable long-lasting OT receptor (OTR) agonist, was associated with a significant reduction of activated microglia, the primary immune cells of the brain. Moreover this reduced microglia reactivity was associated to a long-term neuroprotection. These findings make OT a promising candidate for neonatal neuroprotection through neuroinflammation regulation. However, the causality between the endogenous OT and central inflammation response to injury has not been established and will be further studied by the lab.

Targeting the synapse in Alzheimer’s Disease

Alzheimer’s Disease is characterised by the accumulation of misfolded proteins, namely amyloid and tau, however it is synapse loss which leads to the cognitive impairments associated with the disease. Many studies have focussed on single time points to determine the effects of pathology on synapses however this does not inform on the plasticity of the synapses, that is how they behave in vivo as the pathology progresses. Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of tauopathy[1] (rTg4510) and amyloidopathy[2] (J20). This revealed that pre- and post-synaptic components are differentially affected in both AD models in response to pathology. In the Tg4510 model, differences in the stability and turnover of axonal boutons and dendritic spines immediately prior to neurite degeneration was revealed. Moreover, the dystrophic neurites could be partially rescued by transgene suppression. Understanding the imbalance in the response of pre- and post-synaptic components is crucial for drug discovery studies targeting the synapse in Alzheimer’s Disease. To investigate how sub-types of synapses are affected in human tissue, the Multi-‘omics Atlas Project, a UKDRI initiative to comprehensively map the pathology in human AD, will determine the synaptome changes using imaging and synaptic proteomics in human post mortem AD tissue. The use of multiple brain regions and multiple stages of disease will enable a pseudotemporal profile of pathology and the associated synapse alterations to be determined. These data will be compared to data from preclinical models to determine the functional implications of the human findings, to better inform preclinical drug discovery studies and to develop a therapeutic strategy to target synapses in Alzheimer’s Disease[3].

Reward processing in psychosis: adding meanings to the findings

Much of our daily behavior is driven by rewards. The ability to learn to pursue rewarding experiences is, in fact, an essential metric of mental health. Conversely, reduced capacity to engage in adaptive goal-oriented behavior is the hallmark of apathy, and present in the psychotic disorder. The search for its underlying mechanisms has resulted in findings of profound impairments in learning from rewards and the associated blunted activation in key reward areas of the brain of patients with psychosis. An emerging research field has been relying on digital phenotyping tools and ecological momentary assessments (EMA) that map patients’ current mood, behavior and context in the flow of their daily lives. Using these tools, we have started to see a different picture of apathy, one that is exquisitely driven by the environment. For one, reward sensitivity appears to be blunted by stressors, and exposure to undue chronic stress in the daily life may result in apathy in those predisposed to psychosis. Secondly, even patients with psychosis who exhibit clinically elevated levels of apathy are perfectly capable of seeking out and enjoying social interactions in their daily life, if their environment allows them to do so. The use of digital phenotyping tools in combination with neuroimaging of apathy not only allows us to add meanings to the neurobiological findings, but could also help design rational interventions.

Neuroimaging in human drug addiction: an eye towards intervention development

Drug addiction is a chronically relapsing disorder characterized by compulsive drug use despite catastrophic personal consequences (e.g., loss of family, job) and even when the substance is no longer perceived as pleasurable. In this talk, I will present results of human neuroimaging studies, utilizing a multimodal approach (neuropsychology, functional magnetic resonance imaging, event-related potentials recordings), to explore the neurobiology underlying the core psychological impairments in drug addiction (impulsivity, drive/motivation, insight/awareness) as associated with its clinical symptomatology (intoxication, craving, bingeing, withdrawal). The focus of this talk is on understanding the role of the dopaminergic mesocorticolimbic circuit, and especially the prefrontal cortex, in higher-order executive dysfunction (e.g., disadvantageous decision-making such as trading a car for a couple of cocaine hits) in drug addicted individuals. The theoretical model that guides the presented research is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex, as related to dopaminergic dysfunction, contribute to the core clinical symptoms in drug addiction. Specifically, our multi-modality program of research is guided by the underlying working hypothesis that drug addicted individuals disproportionately attribute reward value to their drug of choice at the expense of other potentially but no-longer-rewarding stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. In this talk I will also explore whether treatment (as usual) and 6-month abstinence enhance recovery in these brain-behavior compromises in treatment seeking cocaine addicted individuals. Promising neuroimaging studies, which combine pharmacological (i.e., oral methylphenidate, or RitalinTM) and salient cognitive tasks or functional connectivity during resting-state, will be discussed as examples for using neuroimaging for empirically guiding the development of effective neurorehabilitation strategies (encompassing cognitive reappraisal and transcranial direct current stimulation) in drug addiction.

Circuit dysfunction and sensory processing in Fragile X Syndrome

To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we have adopted a symptom-to-circuit approach in theFmr1-/- mouse model of Fragile X syndrome (FXS). Using a go/no-go task and in vivo 2-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons in primary visual cortex, and a decrease in the activity of parvalbumin (PV) interneurons. Restoring visually evoked activity in PV cells in Fmr1-/- mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioural performance. Strikingly, human subjects with FXS exhibit similar impairments in visual discrimination as Fmr1-/- mice. These results suggest that manipulating inhibition may help sensory processing in FXS. More recently, we find that the ability of Fmr1-/- mice to perform the visual discrimination task is also drastically impaired in the presence of visual or auditory distractors, suggesting that sensory hypersensitivity may affect perceptual learning in autism.