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SUMMARYState-of-the-art Ca2+ imaging studies that monitor large-scale neural dynamics can produce video datasets ~10 terabytes or more in total size, roughly comparable to ~10,000 Hollywood films. Processing such data volumes requires automated, general-purpose and fast computational methods for cell identification that are robust to a wide variety of noise sources. We introduce EXTRACT, an algorithm that is based on robust estimation theory and uses graphical processing units (GPUs) to extract neural dynamics in computing times up to 10-times faster than imaging durations. We validated EXTRACT on simulated and experimental data and processed 94 public datasets from the Allen Institute Brain Observatory in one day. Showcasing its superiority over past cell-sorting methods at removing noise contaminants, neural activity traces from EXTRACT allow more accurate decoding of animal behavior. Overall, EXTRACT provides neuroscientists with a powerful computational tool matched to the present challenges of neural Ca2+ imaging studies in behaving animals.

Background Evidence has been provided linking neurogenesis to mood disorders. Notably, it has been shown that chronic experimental stress resulting in enhanced depression-like behavior decreases neurogenesis in the dentate gyrus (DG), while antidepressants reverse these stress-induced effects. However, in most studies ''normal'' animals reflecting physiology rather than pathophysiology are used. Therefore, we aimed to investigate neurogenesis in the DG of a mouse model of high-trait anxiety and comorbid depression (HAB), which mimics important features of human psychopathology, and their normal anxiety/ depression (NAB) controls.

Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L-DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery.

Background Impaired extinction of fear is a hallmark of a variety of disabling anxiety disorders including panic disorder, post-traumatic stress disorder, social anxiety disorder and specific phobias. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We recently revealed that 129S1/SvImJ (129S1) mice are unable to extinguish learned fear responses following ‘normal’ fear conditioning, establishing these mice as a clinically relevant model to identify extinction-facilitating targets.

Background Recent evidence suggests that high-frequency deep brain stimulation of the nucleus accumbens (NAcb-DBS) may represent a novel therapeutic strategy for individuals suffering from treatment-resistant depression although the underlying mechanism of action remains largely unknown. Using a unique psychopathological mouse model of enhanced depressionand anxiety-like behavior (HAB) we investigated behavioral and neurobiological effects of NAcb-DBS.