Real-Time Strategy Video Game Experience and Visual Perceptual Learning

Visual perceptual learning (VPL) is defined as long-term improvement in performance on a visual-perception task after visual experiences or training. Early studies have found that VPL is highly specific for the trained feature and location, suggesting that VPL is associated with changes in the early visual cortex. However, the generality of visual skills enhancement attributable to action video-game experience suggests that VPL can result from improvement in higher cognitive skills. If so, experience in real-time strategy (RTS) video-game play, which may heavily involve cognitive skills, may also facilitate VPL. To test this hypothesis, we compared VPL between RTS video-game players (VGPs) and non-VGPs (NVGPs) and elucidated underlying structural and functional neural mechanisms. Healthy young human subjects underwent six training sessions on a texture discrimination task. Diffusion-tensor and functional magnetic resonance imaging were performed before and after training. VGPs performed better than NVGPs in the early phase of training. White-matter connectivity between the right external capsule and visual cortex and neuronal activity in the right inferior frontal gyrus (IFG) and anterior cingulate cortex (ACC) were greater in VGPs than NVGPs and were significantly correlated with RTS video-game experience. In both VGPs and NVGPs, there was task-related neuronal activity in the right IFG, ACC, and striatum, which was strengthened after training. These results indicate that RTS video-game experience, associated with changes in higher-order cognitive functions and connectivity between visual and cognitive areas, facilitates VPL in early phases of training. The results support the hypothesis that VPL can occur without involvement of only visual areas.

SIGNIFICANCE STATEMENT Although early studies found that visual perceptual learning (VPL) is associated with involvement of the visual cortex, generality of visual skills enhancement by action video-game experience suggests that higher-order cognition may be involved in VPL. If so, real-time strategy (RTS) video-game experience may facilitate VPL as a result of heavy involvement of cognitive skills. Here, we compared VPL between RTS video-game players (VGPs) and non-VGPs (NVGPs) and investigated the underlying neural mechanisms. VGPs showed better performance in the early phase of training on the texture discrimination task and greater level of neuronal activity in cognitive areas and structural connectivity between visual and cognitive areas than NVGPs. These results support the hypothesis that VPL can occur beyond the visual cortex.

The Neurodynamics of Affect in the Laboratory Predicts Persistence of Real-World Emotional Responses

Failure to sustain positive affect over time is a hallmark of depression and other psychopathologies, but the mechanisms supporting the ability to sustain positive emotional responses are poorly understood. Here, we investigated the neural correlates associated with the persistence of positive affect in the real world by conducting two experiments in humans: an fMRI task of reward responses and an experience-sampling task measuring emotional responses to a reward obtained in the field. The magnitude of DLPFC engagement to rewards administered in the laboratory predicted reactivity of real-world positive emotion following a reward administered in the field. Sustained ventral striatum engagement in the laboratory positively predicted the duration of real-world positive emotional responses. These results suggest that common pathways are associated with the unfolding of neural processes over seconds and with the dynamics of emotions experienced over minutes. Examining such dynamics may facilitate a better understanding of the brain-behavior associations underlying emotion.

SIGNIFICANCE STATEMENT How real-world emotion, experienced over seconds, minutes, and hours, is instantiated in the brain over the course of milliseconds and seconds is unknown. We combined a novel, real-world experience-sampling task with fMRI to examine how individual differences in real-world emotion, experienced over minutes and hours, is subserved by affective neurodynamics of brain activity over the course of seconds. When winning money in the real world, individuals sustaining positive emotion the longest were those with the most prolonged ventral striatal activity. These results suggest that common pathways are associated with the unfolding of neural processes over seconds and with the dynamics of emotions experienced over minutes. Examining such dynamics may facilitate a better understanding of the brain-behavior associations underlying emotion.

Neural Mechanisms for Acoustic Signal Detection under Strong Masking in an Insect

Communication is fundamental for our understanding of behavior. In the acoustic modality, natural scenes for communication in humans and animals are often very noisy, decreasing the chances for signal detection and discrimination. We investigated the mechanisms enabling selective hearing under natural noisy conditions for auditory receptors and interneurons of an insect. In the studied katydid Mecopoda elongata species-specific calling songs (chirps) are strongly masked by signals of another species, both communicating in sympatry. The spectral properties of the two signals are similar and differ only in a small frequency band at 2 kHz present in the chirping species. Receptors sharply tuned to 2 kHz are completely unaffected by the masking signal of the other species, whereas receptors tuned to higher audio and ultrasonic frequencies show complete masking. Intracellular recordings of identified interneurons revealed two mechanisms providing response selectivity to the chirp. (1) Response selectivity is when several identified interneurons exhibit remarkably selective responses to the chirps, even at signal-to-noise ratios of –21 dB, since they are sharply tuned to 2 kHz. Their dendritic arborizations indicate selective connectivity with low-frequency receptors tuned to 2 kHz. (2) Novelty detection is when a second group of interneurons is broadly tuned but, because of strong stimulus-specific adaptation to the masker spectrum and "novelty detection" to the 2 kHz band present only in the conspecific signal, these interneurons start to respond selectively to the chirp shortly after the onset of the continuous masker. Both mechanisms provide the sensory basis for hearing at unfavorable signal-to-noise ratios.

SIGNIFICANCE STATEMENT Animal and human acoustic communication may suffer from the same "cocktail party problem," when communication happens in noisy social groups. We address solutions for this problem in a model system of two katydids, where one species produces an extremely noisy sound, yet the second species still detects its own song. Using intracellular recording techniques we identified two neural mechanisms underlying the surprising behavioral signal detection at the level of single identified interneurons. These neural mechanisms for signal detection are likely to be important for other sensory modalities as well, where noise in the communication channel creates similar problems. Also, they may be used for the development of algorithms for the filtering of specific signals in technical microphones or hearing aids.

Rapid Visuomotor Corrective Responses during Transport of Hand-Held Objects Incorporate Novel Object Dynamics

Numerous studies have shown that people are adept at learning novel object dynamics, linking applied force and motion, when performing reaching movements with hand-held objects. Here we investigated whether the control of rapid corrective arm responses, elicited in response to visual perturbations, has access to such newly acquired knowledge of object dynamics. Participants first learned to make reaching movements while grasping an object subjected to complex load forces that depended on the distance and angle of the hand from the start position. During a subsequent test phase, we examined grip and load force coordination during corrective arm movements elicited (within ~150 ms) in response to viewed sudden lateral shifts (1.5 cm) in target or object position. We hypothesized that, if knowledge of object dynamics is incorporated in the control of the corrective responses, grip force changes would anticipate the unusual load force changes associated with the corrective arm movements so as to support grasp stability. Indeed, we found that the participants generated grip force adjustments tightly coupled, both spatially and temporally, to the load force changes associated with the arm movement corrections. We submit that recently learned novel object dynamics are effectively integrated into sensorimotor control policies that support rapid visually driven arm corrective actions during transport of hand held objects.

SIGNIFICANCE STATEMENT Previous studies have demonstrated that the motor system can learn, and make use of, internal models of object dynamics to generate feedforward motor commands. However, it is not known whether such internal models are incorporated into rapid, automatic arm movement corrections that compensate for errors that arise during movement. Here we demonstrate, for the first time, that internal models of novel object dynamics are integrated into rapid corrective arm movements made in response to visuomotor perturbations that, importantly, do not directly perturb the object.

Functional Oxygen Sensitivity of Astrocytes

In terrestrial mammals, the oxygen storage capacity of the CNS is limited, and neuronal function is rapidly impaired if oxygen supply is interrupted even for a short period of time. However, oxygen tension monitored by the peripheral (arterial) chemoreceptors is not sensitive to regional CNS differences in partial pressure of oxygen (P_O2) that reflect variable levels of neuronal activity or local tissue hypoxia, pointing to the necessity of a functional brain oxygen sensor. This experimental animal (rats and mice) study shows that astrocytes, the most numerous brain glial cells, are sensitive to physiological changes in P_O2. Astrocytes respond to decreases in P_O2 a few millimeters of mercury below normal brain oxygenation with elevations in intracellular calcium ([Ca²⁺]_i). The hypoxia sensor of astrocytes resides in the mitochondria in which oxygen is consumed. Physiological decrease in P_O2 inhibits astroglial mitochondrial respiration, leading to mitochondrial depolarization, production of free radicals, lipid peroxidation, activation of phospholipase C, IP₃ receptors, and release of Ca²⁺ from the intracellular stores. Hypoxia-induced [Ca²⁺]_i increases in astrocytes trigger fusion of vesicular compartments containing ATP. Blockade of astrocytic signaling by overexpression of ATP-degrading enzymes or targeted astrocyte-specific expression of tetanus toxin light chain (to interfere with vesicular release mechanisms) within the brainstem respiratory rhythm-generating circuits reveals the fundamental physiological role of astroglial oxygen sensitivity; in low-oxygen conditions (environmental hypoxia), this mechanism increases breathing activity even in the absence of peripheral chemoreceptor oxygen sensing. These results demonstrate that astrocytes are functionally specialized CNS oxygen sensors tuned for rapid detection of physiological changes in brain oxygenation.

SIGNIFICANCE STATEMENT Most, if not all, animal cells possess mechanisms that allow them to detect decreases in oxygen availability leading to slow-timescale, adaptive changes in gene expression and cell physiology. To date, only two types of mammalian cells have been demonstrated to be specialized for rapid functional oxygen sensing: glomus cells of the carotid body (peripheral respiratory chemoreceptors) that stimulate breathing when oxygenation of the arterial blood decreases; and pulmonary arterial smooth muscle cells responsible for hypoxic pulmonary vasoconstriction to limit perfusion of poorly ventilated regions of the lungs. Results of the present study suggest that there is another specialized oxygen-sensitive cell type in the body, the astrocyte, that is tuned for rapid detection of physiological changes in brain oxygenation.

SCYL2 Protects CA3 Pyramidal Neurons from Excitotoxicity during Functional Maturation of the Mouse Hippocampus

Neuronal death caused by excessive excitatory signaling, excitotoxicity, plays a central role in neurodegenerative disorders. The mechanisms regulating this process, however, are still incompletely understood. Here we show that the coated vesicle-associated kinase SCYL2/CVAK104 plays a critical role for the normal functioning of the nervous system and for suppressing excitotoxicity in the developing hippocampus. Targeted disruption of Scyl2 in mice caused perinatal lethality in the vast majority of newborn mice and severe sensory-motor deficits in mice that survived to adulthood. Consistent with a neurogenic origin of these phenotypes, neuron-specific deletion of Scyl2 also caused perinatal lethality in the majority of newborn mice and severe neurological defects in adult mice. The neurological deficits in these mice were associated with the degeneration of several neuronal populations, most notably CA3 pyramidal neurons of the hippocampus, which we analyzed in more detail. The loss of CA3 neurons occurred during the functional maturation of the hippocampus and was the result of a BAX-dependent apoptotic process. Excessive excitatory signaling was present at the onset of degeneration, and inhibition of excitatory signaling prevented the degeneration of CA3 neurons. Biochemical fractionation reveals that Scyl2-deficient mice have an altered composition of excitatory receptors at synapses. Our findings demonstrate an essential role for SCYL2 in regulating neuronal function and survival and suggest a role for SCYL2 in regulating excitatory signaling in the developing brain.

SIGNIFICANCE STATEMENT Here we examine the in vivo function of SCYL2, an evolutionarily conserved and ubiquitously expressed protein pseudokinase thought to regulate protein trafficking along the secretory pathway, and demonstrate its importance for the normal functioning of the nervous system and for suppressing excitatory signaling in the developing brain. Together with recent studies demonstrating a role of SCYL1 in preventing motor neuron degeneration, our findings clearly establish the SCY1-like family of protein pseudokinases as key regulators of neuronal function and survival.

VPS35 in Dopamine Neurons Is Required for Endosome-to-Golgi Retrieval of Lamp2a, a Receptor of Chaperone-Mediated Autophagy That Is Critical for {alpha}-Synuclein Degradation and Prevention of Pathogenesis of Parkinson's Disease

Vacuolar protein sorting-35 (VPS35) is essential for endosome-to-Golgi retrieval of membrane proteins. Mutations in the VPS35 gene have been identified in patients with autosomal dominant PD. However, it remains poorly understood if and how VPS35 deficiency or mutation contributes to PD pathogenesis. Here we provide evidence that links VPS35 deficiency to PD-like neuropathology. VPS35 was expressed in mouse dopamine (DA) neurons in substantia nigra pars compacta (SNpc) and STR (striatum)—regions that are PD vulnerable. VPS35-deficient mice exhibited PD-relevant deficits including accumulation of α-synuclein in SNpc-DA neurons, loss of DA transmitter and DA neurons in SNpc and STR, and impairment of locomotor behavior. Further mechanical studies showed that VPS35-deficient DA neurons or DA neurons expressing PD-linked VPS35 mutant (D620N) had impaired endosome-to-Golgi retrieval of lysosome-associated membrane glycoprotein 2a (Lamp2a) and accelerated Lamp2a degradation. Expression of Lamp2a in VPS35-deficient DA neurons reduced α-synuclein, supporting the view for Lamp2a as a receptor of chaperone-mediated autophagy to be critical for α-synuclein degradation. These results suggest that VPS35 deficiency or mutation promotes PD pathogenesis and reveals a crucial pathway, VPS35-Lamp2a-α-synuclein, to prevent PD pathogenesis.

SIGNIFICANCE STATEMENT VPS35 is a key component of the retromer complex that is essential for endosome-to-Golgi retrieval of membrane proteins. Mutations in the VPS35 gene have been identified in patients with PD. However, if and how VPS35 deficiency or mutation contributes to PD pathogenesis remains unclear. We demonstrated that VPS35 deficiency or mutation (D620N) in mice leads to α-synuclein accumulation and aggregation in the substantia nigra, accompanied with DA neurodegeneration. VPS35-deficient DA neurons exhibit impaired endosome-to-Golgi retrieval of Lamp2a, which may contribute to the reduced α-synuclein degradation through chaperone-mediated autophagy. These results suggest that VPS35 deficiency or mutation promotes PD pathogenesis, and reveals a crucial pathway, VPS35-Lamp2a-α-synuclein, to prevent PD pathogenesis.