Sensitivity and responsivity measures for discrimination learning

Serious mental illness occurs in 25% of the general population, with many disorders being neurodevelopmental, lifelong, and debilitating. The wide variation and overlap in symptoms across disorders increases the difficulty of research and treatment development. The NIMH Research Domain of Criteria initiative aims to improve our understanding of the molecular and behavioral consequences of specific neurodevelopmental mechanisms across disorders, enabling targeted treatment development. The transcription factor Specificity Protein 4 (SP4) is important for neurodevelopment and is genetically associated with both schizophrenia and bipolar disorder. Reduced Sp4 expression in mice (hypomorphic) reproduces several characteristics of psychiatric disorders. We further tested the utility of Sp4 hypomorphic mice as a model organism relevant to psychiatric disorders by assessing cognitive control plus effort and decision-making aspects of approach motivation using cross-species-relevant tests. Sp4 hypomorphic mice exhibited impaired attention as measured by the 5-Choice Continuous Performance Test, an effect that was attenuated by glycine type-1 transporter (GlyT-1) inhibition. Hypomorphic mice also exhibited reduced motivation to work for a reward and impaired probabilistic learning. These deficits may stem from affected anticipatory reward, analogous to anhedonia in patients with schizophrenia and other psychiatric disorders. Neither positive valence deficit was attenuated by GlyT-1 treatment, suggesting that these and the attentional deficits stem from different underlying mechanisms. Given the association of SP4 gene with schizophrenia and bipolar disorder, the present studies provide support that personalized GlyT-1 inhibition may treat attentional deficits in neuropsychiatric patients with low SP4 levels.

Section: Drugsmentioning

confidence: 99%

Section: Drugsmentioning

confidence: 99%

GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders

Young

Kamenski

Higa

et al. 2015

“…This index is comparable to the sensitivity index (SI) (Frey and Colliver, 1973) except that VI is based on the relative number of hits and false alarms, whereas SI is calculated using the probabilities for hits and false alarms. Thus, VI values are not confounded by errors of omission.…”

Section: Behavioral Training and Testingmentioning

confidence: 99%

Toward a Neuro-Cognitive Animal Model of the Cognitive Symptoms of Schizophrenia: Disruption of Cortical Cholinergic Neurotransmission Following Repeated Amphetamine Exposure in Attentional Task-Performing, but Not Non-Performing, Rats

Kozak

Martı́nez

Young

et al. 2007

Impairments in attentional functions and capacities represent core aspects of the cognitive symptoms of schizophrenia. Attentional performance has been demonstrated to depend on the integrity and activity of cortical cholinergic inputs. The neurobiological, behavioral, and cognitive effects of repeated exposure to psychostimulants model important aspects of schizophrenia. In the present experiment, prefrontal acetylcholine (ACh) release was measured in attentional task-performing and non-performing rats pretreated with an escalating dosing regimen of amphetamine (AMPH) and following challenges with AMPH. In non-performing rats, pretreatment with AMPH did not affect the increases in ACh release produced by AMPH-challenges. In contrast, attentional task performanceassociated increases in ACh release were attenuated in AMPH-pretreated and AMPH-challenged rats. This effect of repeated AMPH exposure on ACh release was already present before task-onset, suggesting that the loss of cognitive control that characterized these animals' performance was a result of cholinergic dysregulation. The findings indicate that the demonstration of repeated AMPH-induced dysregulation of the prefrontal cholinergic input system depends on interactions between the effects of repeated AMPH exposure and cognitive performance-associated recruitment of this neuronal system. Repeated AMPH-induced disruption of prefrontal cholinergic activity and attentional performance represents a useful model to investigate the cholinergic mechanisms contributing to the cognitive impairments of schizophrenia.

“…To obtain an overall measure of performance that reflects the animals' accuracy in both signal and nonsignal trials, a 'vigilance index' was calculated (VI ¼ 9(hÀf)/2 Â (h + f)À(h + f) 2 )). VI is a modification of the sensitivity index (Frey and Colliver, 1973) and is based on the relative number of correct responses as opposed to the probability for such responses, thereby removing errors of omissions from this index. VI values range from À1 to 1, with a score of 1 indicating that all responses were hits and correct rejections, 0 indicating random lever selection, and À1 reflecting that all responses were misses and false alarms.…”

Section: Measures Of Performancementioning

confidence: 99%

Detection of the Moderately Beneficial Cognitive Effects of Low-Dose Treatment with Haloperidol or Clozapine in an Animal Model of the Attentional Impairments of Schizophrenia

Martı́nez

Sarter

2007

The absence of effective cognition enhancers for the treatment of patients with schizophrenia limits the validation of animal models and behavioral tests used for drug finding and characterization. However, low doses of haloperidol and clozapine were documented to produce moderately beneficial effects in patients. Therefore, this experiment was designed to determine the attentional effects of such treatments in a repeated-amphetamine (AMPH) animal model. Animals were trained in an operant-sustained attention task and underwent a 40-day pretreatment period with saline or increasing doses (1-10 mg per kg) of AMPH. After regaining baseline performance following 10 days of saline treatment, animals were treated with haloperidol (0.025 mg per kg), clozapine (2.5 mg per kg), or vehicle for 10 days. Furthermore, the effects of AMPH challenges (1.0 mg per kg) were assessed. In AMPH-pretreated animals, the administration of AMPH challenges resulted in the disruption of attentional performance. Treatment with haloperidol and clozapine attenuated the detrimental performance effects of these challenges, with clozapine exhibiting more robust attenuation. Furthermore, clozapine, but not haloperidol, impaired the performance of control animals. In contrast, the performance of AMPH-pretreated animals remained unaffected by clozapine. As this animal model detects the moderately beneficial cognitive effects of haloperidol and clozapine, it may be useful for preclinical research designed to detect and characterize treatments for the cognitive symptoms of schizophrenia.