General-relativistic precession in a black-hole binary.

The general-relativistic phenomenon of spin-induced orbital precession has not yet been observed in strong-field gravity. Gravitational-wave observations of binary black holes (BBHs) are prime candidates, as we expect the astrophysical binary population to contain precessing binaries1,2. Imprints of precession have been investigated in several signals3-5, but no definitive identification of orbital precession has been reported in any of the 84 BBH observations so far5-7 by the Advanced LIGO and Virgo detectors8,9. Here we report the measurement of strong-field precession in the LIGO-Virgo-Kagra gravitational-wave signal GW200129. The binary's orbit precesses at a rate ten orders of magnitude faster than previous weak-field measurements from binary pulsars10-13. We also find that the primary black hole is probably highly spinning. According to current binary population estimates, a GW200129-like signal is extremely unlikely, and therefore presents a direct challenge to many current binary-formation models.

Conditioned [corrected] stimulus informativeness governs conditioned stimulus-unconditioned stimulus associability.

In a conditioning protocol, the onset of the conditioned stimulus ([CS]) provides information about when to expect reinforcement (unconditioned stimulus [US]). There are two sources of information from the CS in a delay conditioning paradigm in which the CS-US interval is fixed. The first depends on the informativeness, the degree to which CS onset reduces the average expected time to onset of the next US. The second depends only on how precisely a subject can represent a fixed-duration interval (the temporal Weber fraction). In three experiments with mice, we tested the differential impact of these two sources of information on rate of acquisition of conditioned responding (CS-US associability). In Experiment 1, we showed that associability (the inverse of trials to acquisition) increased in proportion to informativeness. In Experiment 2, we showed that fixing the duration of the US-US interval or the CS-US interval or both had no effect on associability. In Experiment 3, we equated the increase in information produced by varying the C/T ratio with the increase produced by fixing the duration of the CS-US interval. Associability increased with increased informativeness, but, as in Experiment 2, fixing the CS-US duration had no effect on associability. These results are consistent with the view that CS-US associability depends on the increased rate of reward signaled by CS onset. The results also provide further evidence that conditioned responding is temporally controlled when it emerges.

Pharmacologic rescue of motivational deficit in an animal model of the negative symptoms of schizophrenia.

BACKGROUND: Deficits in incentive motivation, the energizing of behavior in pursuit of a goal, occur in many psychiatric disorders including schizophrenia. We previously reported deficits in both cognition and incentive motivation in a transgenic mouse model of increased striatal-specific dopamine D2 receptor (D2R) density (D2R-OE mice). This molecular alteration is observed in patients with schizophrenia, making D2R-OE mice a suitable system to study the cellular and molecular mechanisms of motivation and avolition, as well as a tool for testing potential therapies against motivational deficits. METHODS: Behavioral studies using operant conditioning methods were performed both to further characterize the incentive motivation deficit in D2R-OE mice and test a novel pharmacological treatment target that arose from an unbiased expression study performed using gene chips and was validated by quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. RESULTS: The reluctance of D2R-OE mice to work is due neither to intolerance for low rates of reward, decreased reactivity to reward, nor increased sensitivity to satiety or fatigue but to a difference in willingness to work for reward. As in patients with schizophrenia, this deficit was not ameliorated by D2R blockade, suggesting that reversal of the motivational deficit by switching off the transgene results from molecular changes downstream of D2R overexpression. We observed a reversible increase in serotonin subtype 2C (5-HT2C) receptor expression in D2R-OE mice. Systemic injection of a 5-HT2C receptor antagonist increased incentive motivation in D2R-OE and control mice. CONCLUSIONS: We propose that targeting 5-HT2C receptors may be a useful approach to modulate incentive motivation in psychiatric illness.

Impaired timing precision produced by striatal D2 receptor overexpression is mediated by cognitive and motivational deficits.

Increased striatal dopamine D2 receptor activity is thought to contribute to the pathophysiology of schizophrenia. To model this condition in mice, Kellendonk et al. (2006) generated transgenic mice that selectively overexpress the D2 receptor in striatum (D2OE). Drew et al. (2007) reported that D2OE mice display deficits in interval timing and motivation. The present study further explored the impaired timing in D2OE mice. Experiment 1 assessed the role of motivation in producing timing deficits in the peak procedure and found that performance in D2OE mice was improved by increasing motivation. In addition, performance was impaired in control mice when motivation was decreased. In Experiment 2, we found that D2OE mice have no timing impairment when tested using the bisection task, a procedure in which the measure of timing performance is less influenced by motivation to respond. In Experiment 3, we also used the bisection task and found selective impairment in timing of long durations in D2OE mice. These results suggest that striatal D2 overexpression impairs timing by decreasing motivation and through its impact on working memory and/or sustained attention.

Glutaminase-deficient mice display hippocampal hypoactivity, insensitivity to pro-psychotic drugs and potentiated latent inhibition: relevance to schizophrenia.

Dysregulated glutamatergic neurotransmission has been strongly implicated in the pathophysiology of schizophrenia (SCZ). Recently, presynaptic modulation of glutamate transmission has been shown to have therapeutic promise. We asked whether genetic knockdown of glutaminase (gene GLS1) to reduce glutamatergic transmission presynaptically by slowing the recycling of glutamine to glutamate, would produce a phenotype relevant to SCZ and its treatment. GLS1 heterozygous (GLS1 het) mice showed about a 50% global reduction in glutaminase activity, and a modest reduction in glutamate levels in brain regions relevant to SCZ pathophysiology, but displayed neither general behavioral abnormalities nor SCZ-associated phenotypes. Functional imaging, measuring regional cerebral blood volume, showed hippocampal hypometabolism mainly in the CA1 subregion and subiculum, the inverse of recent clinical imaging findings in prodromal and SCZ patients. GLS1 het mice were less sensitive to the behavioral stimulating effects of amphetamine, showed a reduction in amphetamine-induced striatal dopamine release and in ketamine-induced frontal cortical activation, suggesting that GLS1 het mice are resistant to the effects of these pro-psychotic challenges. Moreover, GLS1 het mice showed clozapine-like potentiation of latent inhibition, suggesting that reduction in glutaminase has antipsychotic-like properties. These observations provide further support for the pivotal role of altered glutamatergic synaptic transmission in the pathophysiology of SCZ, and suggest that presynaptic modulation of the glutamine-glutamate pathway through glutaminase inhibition may provide a new direction for the pharmacotherapy of SCZ.

Transient overexpression of striatal D2 receptors impairs operant motivation and interval timing.

The striatum receives prominent dopaminergic innervation that is integral to appetitive learning, performance, and motivation. Signaling through the dopamine D2 receptor is critical for all of these processes. For instance, drugs with high affinity for the D2 receptor potently alter timing of operant responses and modulate motivation. Recently, in an attempt to model a genetic abnormality encountered in schizophrenia, mice were generated that reversibly overexpress D2 receptors specifically in the striatum (Kellendonk et al., 2006). These mice have impairments in working memory and behavioral flexibility, components of the cognitive symptoms of schizophrenia, that are not rescued when D2 overexpression is reversed in the adult. Here we report that overexpression of striatal D2 receptors also profoundly affects operant performance, a potential index of negative symptoms. Mice overexpressing D2 exhibited impairments in the ability to time food rewards in an operant interval timing task and reduced motivation to lever press for food reward in both the operant timing task and a progressive ratio schedule of reinforcement. The motivational deficit, but not the timing deficit, was rescued in adult mice by reversing D2 overexpression with doxycycline. These results suggest that early D2 overexpression alters the organization of interval timing circuits and confirms that striatal D2 signaling in the adult regulates motivational process. Moreover, overexpression of D2 under pathological conditions such as schizophrenia and Parkinson's disease could give rise to motivational and timing deficits.

Pavlovian contingencies and temporal information.

The effects of altering the contingency between the conditioned stimulus (CS) and the unconditioned stimulus (US) on the acquisition of autoshaped responding was investigated by changing the frequency of unsignaled USs during the intertrial interval. The addition of the unsignaled USs had an effect on acquisition speed comparable with that of massing trials. The effects of these manipulations can be understood in terms of their effect on the amount of information (number of bits) that the average CS conveys to the subject about the timing of the next US. The number of reinforced CSs prior to acquisition is inversely related to the information content of the CS.

The learning curve: implications of a quantitative analysis.

The negatively accelerated, gradually increasing learning curve is an artifact of group averaging in several commonly used basic learning paradigms (pigeon autoshaping, delay- and trace-eye-blink conditioning in the rabbit and rat, autoshaped hopper entry in the rat, plus maze performance in the rat, and water maze performance in the mouse). The learning curves for individual subjects show an abrupt, often step-like increase from the untrained level of responding to the level seen in the well trained subject. The rise is at least as abrupt as that commonly seen in psychometric functions in stimulus detection experiments. It may indicate that the appearance of conditioned behavior is mediated by an evidence-based decision process, as in stimulus detection experiments. If the appearance of conditioned behavior is taken instead to reflect the increase in an underlying associative strength, then a negligible portion of the function relating associative strength to amount of experience is behaviorally visible. Consequently, rate of learning cannot be estimated from the group-average curve; the best measure is latency to the onset of responding, determined for each subject individually.

The first law for slowly evolving horizons.

We study the mechanics of Hayward's trapping horizons, taking isolated horizons as equilibrium states. Zeroth and second laws of dynamic horizon mechanics come from the isolated and trapping horizon formalisms, respectively. We derive a dynamical first law by introducing a new perturbative formulation for dynamic horizons in which "slowly evolving" trapping horizons may be viewed as perturbatively nonisolated.

Effects of dopamine antagonists on the timing of two intervals.

Rats were trained on a two-interval (12 and 36 s) temporal production task (the peak procedure). Test sessions were conducted in which either the D(1) antagonist SCH-23390 (SCH; 0.02, 0.04, 0.06 mg/kg) or the D(2) antagonist haloperidol (HAL; 0.05, 0.1, 0.2 mg/kg) were injected prior to testing. Both drugs affected the amount of responding, but only HAL affected timing. Under HAL, both intervals were overestimated, consistent with a HAL-induced decrease in clock speed. Drug-induced decreases in response output were more profound for the long interval than the short. In addition, there was evidence of HAL- and SCH-induced delays in response initiation that were more severe for the long interval, perhaps owing to its status as a weaker conditioned stimulus.