Dual orexin/hypocretin receptor antagonism attenuates NMDA receptor hypofunction-induced attentional impairments in a rat model of schizophrenia.

Schizophrenia is a neuropsychiatric condition that is associated with impaired attentional processing and performance. Failure to support increasing attentional load may result, in part, from inhibitory failure in attention-relevant cortical regions, and available antipsychotics often fail to address this issue. Orexin/hypocretin receptors are found throughout the brain and are expressed on neurons relevant to both attention and schizophrenia, highlighting them as a potential target to treat schizophrenia-associated attentional dysfunction. In the present experiment, rats (N = 14) trained in a visual sustained attention task that required discrimination of trials which presented a visual signal from trials during which no signal was presented. Once trained, rats were then co-administered the psychotomimetic N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801: 0 or 0.1 mg/kg, intraperitoneal injections) and the dual orexin receptor antagonist filorexant (MK-6096: 0, 0.1, or 1 mM, intracerebroventricular infusions) prior to task performance across six sessions. Dizocilpine impaired overall accuracy during signal trials, slowed reaction times for correctly-responded trials, and increased the number of omitted trials throughout the task. Dizocilpine-induced increases in signal trial deficits, correct response latencies, and errors of omission were reduced following infusions of the 0.1 mM, but not 1 mM, dose of filorexant. As such, orexin receptor blockade may improve attentional deficits in a state of NMDA receptor hypofunction.

Basal forebrain parvalbumin neurons modulate vigilant attention and rescue deficits produced by sleep deprivation.

Attention is impaired in many neuropsychiatric disorders, as well as by sleep disruption, leading to decreased workplace productivity and increased risk of accidents. Thus, understanding the neural substrates is important. Here we test the hypothesis that basal forebrain neurons that contain the calcium-binding protein parvalbumin modulate vigilant attention in mice. Furthermore, we test whether increasing the activity of basal forebrain parvalbumin neurons can rescue the deleterious effects of sleep deprivation on vigilance. A lever release version of the rodent psychomotor vigilance test was used to assess vigilant attention. Brief and continuous low-power optogenetic excitation (1 s, 473 nm @ 5 mW) or inhibition (1 s, 530 nm @ 10 mW) of basal forebrain parvalbumin neurons was used to test the effect on attention, as measured by reaction time, under control conditions and following 8 hr of sleep deprivation by gentle handling. Optogenetic excitation of basal forebrain parvalbumin neurons that preceded the cue light signal by 0.5 s improved vigilant attention as indicated by quicker reaction times. By contrast, both sleep deprivation and optogenetic inhibition slowed reaction times. Importantly, basal forebrain parvalbumin excitation rescued the reaction time deficits in sleep-deprived mice. Control experiments using a progressive ratio operant task confirmed that optogenetic manipulation of basal forebrain parvalbumin neurons did not alter motivation. These findings reveal for the first time a role for basal forebrain parvalbumin neurons in attention, and show that increasing their activity can compensate for disruptive effects of sleep deprivation.

Dual orexin/hypocretin receptor antagonism attenuates attentional impairments in an NMDA receptor hypofunction model of schizophrenia.

Schizophrenia is a neuropsychiatric condition that is associated with impaired attentional processing and performance. Failure to support increasing attentional load may result, in part, from abnormally overactive basal forebrain projections to the prefrontal cortex, and available antipsychotics often fail to address this issue. Orexin/hypocretin receptors are expressed on corticopetal cholinergic neurons, and their blockade has been shown to decrease the activity of cortical basal forebrain outputs and prefrontal cortical cholinergic neurotransmission. In the present experiment, rats (N = 14) trained in a visual sustained attention task that required discrimination of trials which presented a visual signal from trials during which no signal was presented. Once trained, rats were then co-administered the psychotomimetic N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801: 0 or 0.1 mg/kg, intraperitoneal injections) and the dual orexin receptor antagonist filorexant (MK-6096: 0, 0.1, or 1 mM, intracerebroventricular infusions) prior to task performance across six sessions. Dizocilpine impaired overall accuracy during signal trials, slowed reaction times for correctly-responded trials, and increased the number of omitted trials throughout the task. Dizocilpine-induced increases in signal trial deficits, correct response latencies, and errors of omission were reduced following infusions of the 0.1 mM, but not 1 mM, dose of filorexant. Orexin receptor blockade, perhaps through anticholinergic mechanisms, may improve attentional deficits in a state of NMDA receptor hypofunction. Highlights: Schizophrenia is associated with attentional deficits that may stem from abnormally reactive BF projections to the prefrontal cortexOrexin receptor antagonists decrease acetylcholine release and reduce prefrontal cortical activityThe dual orexin receptor antagonist filorexant alleviated impairments of attention following NMDA receptor blockade.

Role of the locus coeruleus and basal forebrain in arousal and attention.

Experimental evidence has implicated multiple neurotransmitter systems in either the direct or indirect modulation of cortical arousal and attention circuitry. In this review, we selectively focus on three such systems: 1) norepinephrine (NE)-containing neurons of the locus coeruleus (LC), 2) acetylcholine (ACh)-containing neurons of the basal forebrain (BF), and 3) parvalbumin (PV)-containing gamma-aminobutyric acid neurons of the BF. Whereas BF-PV neurons serve as a rapid and transient arousal system, LC-NE and BF-ACh neuromodulation are typically activated on slower but longer-lasting timescales. Recent findings suggest that the BF-PV system serves to rapidly respond to even subtle sensory stimuli with a microarousal. We posit that salient sensory stimuli, such as those that are threatening or predict the need for a response, will quickly activate the BF-PV system and subsequently activate both the BF-ACh and LC-NE systems if the circumstances require longer periods of arousal and vigilance. We suggest that NE and ACh have overlapping psychological functions with the main difference being the precise internal/environmental sensory situations/contexts that recruit each neurotransmitter system - a goal for future research to determine. Implications of dysfunction of each of these three attentional systems for our understanding of neuropsychiatric conditions are considered. Finally, the contemporary availability of research tools to selectively manipulate and measure the activity of these distinctive neuronal populations promises to answer longstanding questions, such as how various arousal systems influence downstream decision-making and motor responding.

Neuropharmacology of attention.

Early philosophers and psychologists defined and began to describe attention. Beginning in the 1950's, numerous models of attention were developed. This corresponded with an increased understanding of pharmacological approaches to manipulate neurotransmitter systems. The present review focuses on the knowledge that has been gained about these neurotransmitter systems with respect to attentional processing, with emphasis on the functions mediated within the medial prefrontal cortex. Additionally, the use of pharmacotherapies to treat psychiatric conditions characterized by attentional dysfunction are discussed. Future directions include developing a more comprehensive understanding of the neural mechanisms underlying attentional processing and novel pharmacotherapeutic targets for conditions characterized by aberrant attentional processing.