Memory and cognition in schizophreniaGuo, J.; Ragland, J.; Carter, C.
doi: 10.1038/s41380-018-0231-1pmid: 30242229
Episodic memory deficits are consistently documented as a core aspect of cognitive dysfunction in schizophrenia patients, present from the onset of the illness and strongly associated with functional disability. Over the past decade, research using approaches from experimental cognitive neuroscience revealed disproportionate episodic memory impairments in schizophrenia (Sz) under high cognitive demand relational encoding conditions and relatively unimpaired performance under item-specific encoding conditions. These specific deficits in component processes of episodic memory reflect impaired activation and connectivity within specific elements of frontal-medial temporal lobe circuits, with a central role for the dorsolateral prefrontal cortex (DLPFC), relatively intact function of ventrolateral prefrontal cortex and variable results in the hippocampus. We propose that memory deficits can be understood within the broader context of cognitive deficits in Sz, where impaired DLPFC-related cognitive control has a broad impact across multiple cognitive domains. The therapeutic implications of these findings are discussed.
PPARγ agonists: potential treatment for autism spectrum disorder by inhibiting the canonical WNT/β-catenin pathwayVallée, Alexandre; Vallée, Jean-Noël; Lecarpentier, Yves
doi: 10.1038/s41380-018-0131-4pmid: 30104725
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by a deficit in social interactions and communication with repetitive and restrictive behavior. No curative treatments are available for ASD. Pharmacological treatments do not address the core ASD behaviors, but target comorbid symptoms. Dysregulation of the core neurodevelopmental pathways is associated with the clinical presentation of ASD, and the canonical WNT/β-catenin pathway is one of the major pathways involved. The canonical WNT/β-catenin pathway participates in the development of the central nervous system, and its dysregulation involves developmental cognitive disorders. In numerous tissues, the canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPARγ) act in an opposed manner. In ASD, the canonical WNT/β-catenin pathway is increased while PPARγ seems to be decreased. PPARγ agonists present a beneficial effect in treatment for ASD children through their anti-inflammatory role. Moreover, they induce the inhibition of the canonical WNT/β-catenin pathway in several pathophysiological states. We focus this review on the hypothesis of an opposed interplay between PPARγ and the canonical WNT/β-catenin pathway in ASD and the potential role of PPARγ agonists as treatment for ASD.
Molecular windows into the human brain for psychiatric disordersEgervari, Gabor; Kozlenkov, Alexey; Dracheva, Stella; Hurd, Yasmin
doi: 10.1038/s41380-018-0125-2pmid: 29955163
Delineating the pathophysiology of psychiatric disorders has been extremely challenging but technological advances in recent decades have facilitated a deeper interrogation of molecular processes in the human brain. Initial candidate gene expression studies of the postmortem brain have evolved into genome wide profiling of the transcriptome and the epigenome, a critical regulator of gene expression. Here, we review the potential and challenges of direct molecular characterization of the postmortem human brain, and provide a brief overview of recent transcriptional and epigenetic studies with respect to neuropsychiatric disorders. Such information can now be leveraged and integrated with the growing number of genome-wide association databases to provide a functional context of trait-associated genetic variants linked to psychiatric illnesses and related phenotypes. While it is clear that the field is still developing and challenges remain to be surmounted, these recent advances nevertheless hold tremendous promise for delineating the neurobiological underpinnings of mental diseases and accelerating the development of novel medication strategies.
Neuroimaging of reward mechanisms in Gambling disorder: an integrative reviewClark, Luke; Boileau, Isabelle; Zack, Martin
doi: 10.1038/s41380-018-0230-2pmid: 30214041
Gambling disorder (GD) was reclassified as a behavioral addiction in the DSM-5 and shares clinical and behavioral features with substance use disorders (SUDs). Neuroimaging studies of GD hold promise in isolating core features of the addiction syndrome, avoiding confounding effects of drug neurotoxicity. At the same time, a neurobiologically-grounded theory of how behaviors like gambling can become addictive remains lacking, posing a significant hurdle for ongoing decisions in addiction nosology. This article integrates research on reward-related brain activity (functional MRI) and neurotransmitter function (PET) in GD, alongside the consideration of structural MRI data as to whether these signals more likely reflect pre-existing vulnerability or neuroadaptive change. Where possible, we point to qualitative similarities and differences with established markers for SUDs. Structural MRI studies indicate modest changes in regional gray matter volume and diffuse reductions in white matter integrity in GD, contrasting with clear structural deterioration in SUDs. Functional MRI studies consistently identify dysregulation in reward-related circuitry (primarily ventral striatum and medial prefrontal cortex), but evidence is mixed as to the direction of these effects. The need for further parsing of reward sub-processes is emphasized, including anticipation vs outcome, gains vs. losses, and disorder-relevant cues vs natural rewards. Neurotransmitter PET studies indicate amplified dopamine (DA) release in GD, in the context of minimal differences in baseline DA D2 receptor binding, highlighting a distinct profile from SUDs. Preliminary work has investigated further contributions of opioids, GABA and serotonin. Neuroimaging data increasingly highlight divergent profiles in GD vs. SUDs. The ability of gambling to perpetually activate DA (via maximal uncertainty) may contribute to neuroimaging similarities between GD and SUDs, whereas the supra-physiological DA effects of drugs may partly explain differences in the neuroimaging profile of the two syndromes. Coupled with consistent observations of correlations with gambling severity and related clinical variables within GD samples, the overall pattern of effects is interpreted as a likely combination of shared vulnerability markers across GD and SUDs, but with further experience-dependent neuroadaptive processes in GD.
Cholinergic regulation of mood: from basic and clinical studies to emerging therapeuticsDulawa, Stephanie; Janowsky, David
doi: 10.1038/s41380-018-0219-xpmid: 30120418
Mood disorders are highly prevalent and are the leading cause of disability worldwide. The neurobiological mechanisms underlying depression remain poorly understood, although theories regarding dysfunction within various neurotransmitter systems have been postulated. Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate suggesting that the cholinergic system has a important role in mood regulation. In particular, the finding that the antimuscarinic agent, scopolamine, exerts fast-onset and sustained antidepressant effects in depressed humans has led to a renewal of interest in the cholinergic system as an important player in the neurochemistry of major depression and bipolar disorder. Here, we synthesize current knowledge regarding the modulation of mood by the central cholinergic system, drawing upon studies from human postmortem brain, neuroimaging, and drug challenge investigations, as well as animal model studies. First, we describe an illustrative series of early discoveries which suggest a role for acetylcholine in the pathophysiology of mood disorders. Then, we discuss more recent studies conducted in humans and/or animals which have identified roles for both acetylcholinergic muscarinic and nicotinic receptors in different mood states, and as targets for novel therapies.
SSRIs target prefrontal toraphe circuits during development modulating synaptic connectivity and emotional behaviorSoiza-Reilly, M.; Meye, F.; Olusakin, J.; Telley, L.; Petit, E.; Chen, X.; Mameli, M.; Jabaudon, D.; Sze, J.-Y.; Gaspar, P.
doi: 10.1038/s41380-018-0260-9pmid: 30279456
Antidepressants that block the serotonin transporter, (Slc6a4/SERT), selective serotonin reuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-term effects when administered during perinatal periods, increasing the risk to develop anxiety and depression. The basis for this developmental effect is not known. Here, we show that during an early postnatal period in mice (P0–P10), Slc6a4/SERT is transiently expressed in a subset of layer 5–6 pyramidal neurons of the prefrontal cortex (PFC). PFC-SERT+ neurons establish glutamatergic synapses with subcortical targets, including the serotonin (5-HT) and GABA neurons of the dorsal raphe nucleus (DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period of PFC Slc6a4/SERT expression. Complete or cortex-specific ablation of SERT increases the number of functional PFC glutamate synapses on both 5-HT and GABA neurons in the DRN. This PFC-to-DRN hyperinnervation is replicated by early-life exposure to the SSRI, fluoxetine (from P2 to P14), that also causes anxiety/depressive-like symptoms. We show that pharmacogenetic manipulation of PFC-SERT+ neuron activity bidirectionally modulates these symptoms, suggesting that PFC hypofunctionality has a causal role in these altered responses to stress. Overall, our data identify specific PFC descending circuits that are targets of antidepressant drugs during development. We demonstrate that developmental expression of SERT in this subset of PFC neurons controls synaptic maturation of PFC-to-DRN circuits, and that remodeling of these circuits in early life modulates behavioral responses to stress in adulthood.