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COGOPTO Report Summary

Project ID: 337069
Funded under: FP7-IDEAS-ERC
Country: Sweden

Mid-Term Report Summary - COGOPTO (The role of parvalbumin interneurons in cognition and behavior)

Cognition is a collective term for complex but sophisticated mental processes such as attention, learning, social interaction, language production, decision making and other executive functions. For normal brain function, these higher-order functions need to be aptly regulated and controlled, and the physiology and cellular substrates for cognitive functions are under intense investigation. The loss of cognitive control is intricately related to pathological states such as schizophrenia, depression, attention deficit hyperactive disorder (ADHD) and addiction. The prefrontal cortex (PFC) in the frontal lobes is the most elaborate cortical region in primates. The PFC receives projections from all sensory systems, motor systems and many subcortical structures, and is pivotal to the integration and coordination of information received from the external world and internally generated. Simple, automatic behaviors do not depend on PFC, but PFC is important when behavior must be guided by internal intentions, often referred to as goal-directed behavior. In line with this, the PFC has been shown to be required for cognitive processes, and PFC is regarded as integral to cognitive control. A large body of work indicates that cognitive control is dependent on the integrity of local neural synchrony mediated by cortical interneuron networks and actuated by the balance of different neuromodulators. The CogOpto project aims to functionally determine the specific role the parvalbumin (PV) interneurons and the neuromodulator dopamine in fundamental aspects of cognition, and in behavior.

Attention plays a crucial role in our ability to organize thoughts and actions in meaningful behavior - attention allows for stimulus selection, response selection and also let us monitor our performance. On a neurophysiological level, attention biases processing of certain neural representations at the expense of others. As a result, behaviorally relevant information is amplified while distracting or irrelevant information is suppressed. Attentional mechanisms are thought to be regulated by high-order cortical areas, like the PFC, which has key role in selecting relevant information. The cortical inhibitory interneurons expressing PV have repetitively been implicated in a variety of neurological and psychiatric diseases. The links are especially strong in schizophrenia, a disabling mental disorder with well-defined impairments in the control of attention. However, despite many intersecting lines of circumstantial evidence, proof for a function of inhibitory PFC PV neurons in attention has been lacking. To tackle this we have in the CogOpto project characterized the recruitment and firing modulation of PV neurons and excitatory pyramidal neurons in the medial PFC (mPFC) in mice performing a demanding attention task, the 3-choice serial reaction time task (3-CSRTT). The 3-CSRTT is a widely employed rodent attention task building on tests of sustained attention originally developed for humans, and is identified as having high construct validity. We found that mPFC PV neurons uniformly display increased firing during attention, and that the level of PV firing correlates to the level of attention, with the highest activity reflecting successful attentional processing and subsequent successful execution of goal-directed behavior. To prove a function of mPRC PV neurons in the control of attention we employed the novel inhibitory light-activated chloride channel SwiChR. Optogenetic silencing of PV neurons during attentional processing had detrimental effects on the behavior, leading to a doubling of the number of omitted behavioral responses due to inattentiveness. We further employed optogenetics to forcefully synchronize the mPFC PV neurons, and found activity patterns that could impair and enhance attentional processing, respectively. Importantly, enhanced attention and behavior were seen when the PV neurons were driven in a frequency typical of gamma oscillations (30-40 Hz). Increased cortical gamma oscillations are a signature of cognitive processing, and impaired induction of gamma oscillations have been documented in individuals affected by e.g. schizophrenia. Our data support the view that oscillations in the gamma range benefit cortical processing and behavior. Our findins further suggest that cell-type-specific manipulations can be used for enhancement of cortical computations and cognition.

Attention plays a crucial role in our ability to organize thoughts and actions in meaningful behavior - attention allows for stimulus selection, response selection and also let us monitor our performance. On a neurophysiological level, attention biases processing of certain neural representations at the expense of others. As a result, behaviorally relevant information is amplified while distracting or irrelevant information is suppressed. Attentional mechanisms are thought to be regulated by high-order cortical areas, like the PFC, which has key role in selecting relevant information.

The cortical inhibitory interneurons expressing PV have repetitively been implicated in a variety of neurological and psychiatric diseases. The links are especially strong in schizophrenia, a disabling mental disorder with well-defined impairments in the control of attention. However, despite many intersecting lines of circumstantial evidence, proof for a function of inhibitory PFC PV neurons in attention has been lacking. To tackle this we have in the CogOpto project characterized the recruitment and firing modulation of PV neurons and excitatory pyramidal neurons in the medial PFC (mPFC) in mice performing a demanding attention task, the 3-choice serial reaction time task (3-CSRTT). The 3-CSRTT is a widely employed rodent attention task building on tests of sustained attention originally developed for humans, and is identified as having high construct validity. We found that mPFC PV neurons uniformly display increased firing during attention, and that the level of PV firing correlates to the level of attention, with the highest activity reflecting successful attentional processing and subsequent successful execution of a goal-directed behavior. To prove a function of mPRC PV neurons in the control of attention we employed the novel inhibitory light-activated chloride channel SwiChR. Optogenetic silencing of PV neurons during attentional processing had detrimental effects on the behavior, leading to a doubling of the number of omitted behavioral responses due to inattentiveness. We further employed optogenetics to forcefully synchronize the mPFC PV neurons, and found activity patterns that could impair and enhance attentional processing, respectively. Importantly, enhanced attention and behavior were seen when the PV neurons were driven in a frequency typical of gamma oscillations (30-40 Hz). Increased cortical gamma oscillations are a signature of cognitive processing, and impaired induction of gamma oscillations have been documented in individuals affected by e.g. schizophrenia. Our data support the view that cortical gamma oscillations

Contact

Asa Garmager
Tel.: +46 8 52487855
E-mail
Record Number: 191608 / Last updated on: 2016-11-21
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