Prospective and retrospective duration memory in the hippocampus: is time in the foreground or background?

Psychologists have long distinguished between prospective and retrospective timing to highlight the difference between our sense of duration during an experience in passing and our sense of duration in hindsight. Humans and other animals use prospective timing in the seconds-to-minutes range in order to learn durations, and can organize their behaviour based upon this knowledge when they know that duration information will be important ahead of time. By contrast, when durations are estimated after the fact, thus precluding the subject from consciously attending to temporal information, duration information must be extracted from other memory representations. The accumulated evidence from prospective timing research has generally led to the hippocampus (HPC) being casted in a supporting role with prefrontal–striatal, cortical or cerebellar circuits playing the lead. Here, I review findings from the animal and human literature that have led to this conclusion and consider that the contribution of the HPC to duration memory is understated because we have little understanding about how we remember duration.     

Automated,Quantitative Cognitive/Behavioral Screening of Mice: For Genetics,Pharmacology, Animal Cognition and Undergraduate Instruction

We describe a high-throughput, high-volume, fully automated, live-in 24/7 behavioral testing system for assessing the effects of genetic and pharmacological manipulations on basic mechanisms of cognition and learning in mice. A standard polypropylene mouse housing tub is connected through an acrylic tube to a standard commercial mouse test box. The test box has 3 hoppers, 2 of which are connected to pellet feeders. All are internally illuminable with an LED and monitored for head entries by infrared (IR) beams. Mice live in the environment, which eliminates handling during screening. They obtain their food during two or more daily feeding periods by performing in operant (instrumental) and Pavlovian (classical) protocols, for which we have written protocol-control software and quasi-real-time data analysis and graphing software. The data analysis and graphing routines are written in a MATLAB-based language created to simplify greatly the analysis of large time-stamped behavioral and physiological event records and to preserve a full data trail from raw data through all intermediate analyses to the published graphs and statistics within a single data structure. The data-analysis code harvests the data several times a day and subjects it to statistical and graphical analyses, which are automatically stored in the "cloud" and on in-lab computers. Thus, the progress of individual mice is visualized and quantified daily. The data-analysis code talks to the protocol-control code, permitting the automated advance from protocol to protocol of individual subjects. The behavioral protocols implemented are matching, autoshaping, timed hopper-switching, risk assessment in timed hopper-switching, impulsivity measurement, and the circadian anticipation of food availability. Open-source protocol-control and data-analysis code makes the addition of new protocols simple. Eight test environments fit in a 48 in x 24 in x 78 in cabinet; two such cabinets (16 environments) may be controlled by one computer.     

Minutes,days and years: molecular interactions among different scales of biological timing

Biological clocks are genetically encoded oscillators that allow organisms to keep track of their environment. Among them, the circadian system is a highly conserved timing structure that regulates several physiological, metabolic and behavioural functions with periods close to 24 h. Time is also crucial for everyday activities that involve conscious time estimation. Timing behaviour in the second-to-minutes range, known as interval timing, involves the interaction of cortico-striatal circuits. In this review, we summarize current findings on the neurobiological basis of the circadian system, both at the genetic and behavioural level, and also focus on its interactions with interval timing and seasonal rhythms, in order to construct a multi-level biological clock.     

What is all the noise about in interval timing?

Cognitive processes such as decision-making, rate calculation and planning require an accurate estimation of durations in the supra-second range—interval timing. In addition to being accurate, interval timing is scale invariant: the time-estimation errors are proportional to the estimated duration. The origin and mechanisms of this fundamental property are unknown. We discuss the computational properties of a circuit consisting of a large number of (input) neural oscillators projecting on a small number of (output) coincidence detector neurons, which allows time to be coded by the pattern of coincidental activation of its inputs. We showed analytically and checked numerically that time-scale invariance emerges from the neural noise. In particular, we found that errors or noise during storing or retrieving information regarding the memorized criterion time produce symmetric, Gaussian-like output whose width increases linearly with the criterion time. In contrast, frequency variability produces an asymmetric, long-tailed Gaussian-like output, that also obeys scale invariant property. In this architecture, time-scale invariance depends neither on the details of the input population, nor on the distribution probability of noise.     

GRPR在宫颈疾病中的表达及临床意义

目的：研究胃泌素释放肽受体（GRPR）在正常宫颈组织、宫颈上皮内瘤样病变（CIN）、宫颈癌中的表达,探讨GRPR在促癌发生和癌生长等方面的生物学功能。方法：采用免疫组化SP法检测GRPR在28例宫颈癌、51例宫颈上皮内瘤变和15例正常宫颈组织中的表达情况,其中以正常宫颈组织作为对照。结果：在正常宫颈和宫颈癌组织中,GRPR阳性表达率分别为20%和92.9%。GRPR在CINⅠ、CINⅡ、CINⅢ中阳性表达呈上升趋势,差别无统计学意义。宫颈癌组的不同临床分期、有无淋巴结转移组间比较,GRPR的阳性表达率均有显著性差异,并随病情严重程度的增加,阳性率增高,其表达强度呈显著正相关。结论：GRPR的过度表达与宫颈癌的发生、发展有关,是宫颈癌发生的早期事件,其检测可作为评估宫颈癌恶性程度、判断预后及指导治疗的重要参考指标。     

Time-based reward maximization

Humans and animals time intervals from seconds to minutes with high accuracy but limited precision. Consequently, time-based decisions are inevitably subjected to our endogenous timing uncertainty, and thus require temporal risk assessment. In this study, we tested temporal risk assessment ability of humans when participants had to withhold each subsequent response for a minimum duration to earn reward and each response reset the trial time. Premature responses were not penalized in Experiment 1 but were penalized in Experiment 2. Participants tried to maximize reward within a fixed session time (over eight sessions) by pressing a key. No instructions were provided regarding the task rules/parameters. We evaluated empirical performance within the framework of optimality that was based on the level of endogenous timing uncertainty and the payoff structure. Participants nearly tracked the optimal target inter-response times (IRTs) that changed as a function of the level of timing uncertainty and maximized the reward rate in both experiments. Acquisition of optimal target IRT was rapid and abrupt without any further improvement or worsening. These results constitute an example of optimal temporal risk assessment performance in a task that required finding the optimal trade-off between the ‘speed’ (timing) and ‘accuracy’ (reward probability) of timed responses for reward maximization.     

Cognitive assessment of mice strains heterozygous for cell-adhesion genes reveals strain-specific alterations in timing

We used a fully automated system for the behavioural measurement of physiologically meaningful properties of basic mechanisms of cognition to test two strains of heterozygous mutant mice, Bfc (batface) and L1, and their wild-type littermate controls. Both of the target genes are involved in the establishment and maintenance of synapses. We find that the Bfc heterozygotes show reduced precision in their representation of interval duration, whereas the L1 heterozygotes show increased precision. These effects are functionally specific, because many other measures made on the same mice are unaffected, namely: the accuracy of matching temporal investment ratios to income ratios in a matching protocol, the rate of instrumental and classical conditioning, the latency to initiate a cued instrumental response, the trials on task and the impulsivity in a switch paradigm, the accuracy with which mice adjust timed switches to changes in the temporal constraints, the days to acquisition, and mean onset time and onset variability in the circadian anticipation of food availability.     

Influence of the interstimulus interval on temporal processing and learning: testing the state-dependent network model

The ability to determine the interval and duration of sensory events is fundamental to most forms of sensory processing, including speech and music perception. Recent experimental data support the notion that different mechanisms underlie temporal processing in the subsecond and suprasecond range. Here, we examine the predictions of one class of subsecond timing models: state-dependent networks. We establish that the interval between the comparison and the test interval, interstimulus interval (ISI), in a two-interval forced-choice discrimination task, alters the accuracy of interval discrimination but not the point of subjective equality—i.e. while timing was impaired, subjective time contraction or expansion was not observed. We also examined whether the deficit in temporal processing produced by short ISIs can be reduced by learning, and determined the generalization patterns. These results show that training subjects on a task using a short or long ISI produces dramatically different generalization patterns, suggesting different forms of perceptual learning are being engaged. Together, our results are consistent with the notion that timing in the range of hundreds of milliseconds is local as opposed to centralized, and that rapid stimulus presentation rates impair temporal discrimination. This interference is, however, decreased if the stimuli are presented to different sensory channels.     

Amphetamine affects the start of responding in the peak interval timing task

In this paper we investigate how amphetamine affects performance in a PI task by comparing two analyses of responding during peak trials. After training on 24 s fixed interval (FI-24) with 96 s peak trials, rats were given amphetamine for 4 consecutive days at doses of .5 and 1.0 mg/kg. Responses during peak trials were fitted with a Gaussian distribution to estimate the expected time of reinforcement from the peak time. A single trials analysis was also performed to determine the start time and stop time of the transition into and out of a high rate of responding on each peak trial. Amphetamine significantly decreased peak times as measured with the Gaussian curve fitting. However, in the single trials analysis, animals initiated responding significantly earlier, but did not stop responding earlier. Thus, fitting a Gaussian to the average performance across trials sometimes provides a different characterization of the timing process than does analyzing the start and stop of responding on individual trials. In the current experiment, the latter approach provided a more precise characterization of the effects of amphetamine on response timing.     

Zebrafish forebrain and temporal conditioning

The rise of zebrafish as a neuroscience research model organism, in conjunction with recent progress in single-cell resolution whole-brain imaging of larval zebrafish, opens a new window of opportunity for research on interval timing. In this article, we review zebrafish neuroanatomy and neuromodulatory systems, with particular focus on identifying homologies between the zebrafish forebrain and the mammalian forebrain. The neuroanatomical and neurochemical basis of interval timing is summarized with emphasis on the potential of using zebrafish to reveal the neural circuits for interval timing. The behavioural repertoire of larval zebrafish is reviewed and we demonstrate that larval zebrafish are capable of expecting a stimulus at a precise time point with minimal training. In conclusion, we propose that interval timing research using zebrafish and whole-brain calcium imaging at single-cell resolution will contribute to our understanding of how timing and time perception originate in the vertebrate brain from the level of single cells to circuits.     

Sleep timing is more important than sleep length or quality for medical school performance

Overwhelming evidence supports the importance of sleep for memory consolidation. Medical students are often deprived of sufficient sleep due to large amounts of clinical duties and university load, we therefore investigated how study and sleep habits influence university performance. We performed a questionnaire-based study with 31 medical students of the University of Munich (second and third clinical semesters; surgery and internal medicine). The students kept a diary (in 30-min bins) on their daily schedules (times when they studied by themselves, attended classes, slept, worked on their thesis, or worked to earn money). The project design involved three 2-wk periods (A: during the semester; B: directly before the exam period—pre-exam; C: during the subsequent semester break). Besides the diaries, students completed once questionnaires about their sleep quality (Pittsburgh Sleep Quality Index [PSQI]), their chronotype (Munich Chronotype Questionnaire [MCTQ]), and their academic history (previous grades, including the previously achieved preclinical board exam [PBE]). Analysis revealed significant correlations between the actual sleep behavior during the semester (MS_diary; mid-sleep point averaged from the sleep diaries) during the pre-exam period and the achieved grade (p = 0.002) as well as between the grades of the currently taken exam and the PBE (p = 0.002). A regression analysis with MS_diary pre-exam and PBE as predictors in a model explained 42.7% of the variance of the exam grade (effect size 0.745). Interestingly, MS_diary—especially during the pre-exam period—was the strongest predictor for the currently achieved grade, along with the preclinical board exam as a covariate, whereas the chronotype did not significantly influence the exam grade.     

Phenology, seasonal timing and circannual rhythms: towards a unified framework

Phenology refers to the periodic appearance of life-cycle events and currently receives abundant attention as the effects of global change on phenology are so apparent. Phenology as a discipline observes these events and relates their annual variation to variation in climate. But phenology is also studied in other disciplines, each with their own perspective. Evolutionary ecologists study variation in seasonal timing and its fitness consequences, whereas chronobiologists emphasize the periodic nature of life-cycle stages and their underlying timing programmes (e.g. circannual rhythms). The (neuro-) endocrine processes underlying these life-cycle events are studied by physiologists and need to be linked to genes that are explored by molecular geneticists. In order to fully understand variation in phenology, we need to integrate these different perspectives, in particular by combining evolutionary and mechanistic approaches. We use avian research to characterize different perspectives and to highlight integration that has already been achieved. Building on this work, we outline a route towards uniting the different disciplines in a single framework, which may be used to better understand and, more importantly, to forecast climate change impacts on phenology.