NrCAM-deficient mice exposed to chronic stress exhibit disrupted latent inhibition, a hallmark of schizophrenia.

The neuronal cell adhesion molecule (NrCAM) is widely expressed and has important physiological functions in the nervous system across the lifespan, from axonal growth and guidance to spine and synaptic pruning, to organization of proteins at the nodes of Ranvier. NrCAM lies at the core of a functional protein network where multiple targets (including NrCAM itself) have been associated with schizophrenia. Here we investigated the effects of chronic unpredictable stress on latent inhibition, a measure of selective attention and learning which shows alterations in schizophrenia, in NrCAM knockout (KO) mice and their wild-type littermate controls (WT). Under baseline experimental conditions both NrCAM KO and WT mice expressed robust latent inhibition (p = 0.001). However, following chronic unpredictable stress, WT mice (p = 0.002), but not NrCAM KO mice (F < 1), expressed latent inhibition. Analyses of neuronal activation (c-Fos positive counts) in key brain regions relevant to latent inhibition indicated four types of effects: a single hit by genotype in IL cortex (p = 0.0001), a single hit by stress in Acb-shell (p = 0.031), a dual hit stress x genotype in mOFC (p = 0.008), vOFC (p = 0.020), and Acb-core (p = 0.032), and no effect in PrL cortex (p > 0.141). These results indicating a pattern of differential effects of genotype and stress support a complex stress × genotype interaction model and a role for NrCAM in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders.

Resource Allocation in the Noise-Free Striatal Beat Frequency Model of Interval Timing.

The Striatal Beat Frequency (SBF) model of interval timing uses many neural oscillators, presumably located in the frontal cortex (FC), to produce beats at a specific criterion time Tc. The coincidence detection produces the beats in the basal ganglia spiny neurons by comparing the current state of the FC neural oscillators against the long-term memory values stored at reinforcement time Tc. The neurobiologically realistic SBF model has been previously used for producing precise and scalar timing in the presence of noise. Here we simplified the SBF model to gain insight into the problem of resource allocation in interval timing networks. Specifically, we used a noise-free SBF model to explore the lower limits of the number of neural oscillators required for producing accurate timing. Using abstract sine-wave neural oscillators in the SBF-sin model, we found that the lower limit of the number of oscillators needed is proportional to the criterion time Tc and the frequency span (fmax - fmin) of the FC neural oscillators. Using biophysically realistic Morris-Lecar model neurons in the SBF-ML model, the lower bound increased by one to two orders of magnitude compared to the SBF-sin model.

Not All Mice Are Created Equal: Interval Timing Accuracy and Scalar Timing in 129, Swiss-Webster, and C57Bl/6 Mice.

Many species, including humans, show both accurate timing-appropriate time estimation in the seconds to minutes range-and scalar timing-time estimation error varies linearly with estimated duration. Behavioral paradigms aimed at investigating interval timing are expected to evaluate these dissociable characteristics of timing. However, when evaluating interval timing in models of neuropsychiatric disease, researchers are confronted with a lack of adequate studies about the parent (background) strains, since accuracy and scalar timing have only been demonstrated for the C57Bl/6 strain of mice (Buhusi et al., 2009). We used a peak-interval procedure with three intervals-a protocol in which other species, including humans, demonstrate accurate, scalar timing-to evaluate timing accuracy and scalar timing in three strains of mice frequently used in genetic and behavioral studies: 129, Swiss-Webster, and C57Bl/6. C57Bl/6 mice showed accurate, scalar timing, while 129 and Swiss-Webster mice showed departures from accuracy and/or scalar timing. Results suggest that the genetic background / strain of the mouse is a critical variable for studies investigating interval timing in genetically-engineered mice. Our study validates the PI procedure with multiple intervals as a proper technique, and the C57Bl/6 strain as the most suitable genetic background to date for behavioral investigations of interval timing in genetically engineered mice modeling human disorders. In contrast, studies using mice in 129, Swiss-Webster, or mixed-background strains should be interpreted with caution, and thorough investigations of accuracy and scalar timing should be conducted before a less studied strain of mouse is considered for use in timing studies.

A timely glimpse of memories to come.

Research in the last century has provided insight into the systems, cellular, and molecular processes involved in the formation, storage, recall, and update of memory engrams - the physical manifestation of the long sought-after philosophical and psychological concept of memory traces. Recent technologies allow scientists to visualize the key molecular players involved in segregating, ordering, and linking memories close in time, for future treatment of "disorders of the engram" where memory linking is deficient (e.g., cognitive aging or Alzheimer's) or excessive (e.g., PTSD).

Brain-Derived Neurotrophic Factor Val66Met Genotype Modulates Latent Inhibition: Relevance for Schizophrenia.

BACKGROUND AND HYPOTHESIS: Latent inhibition (LI) is a measure of selective attention and learning relevant to Schizophrenia (SZ), with 2 abnormality poles: Disrupted LI in acute SZ, thought to underlie positive symptoms, and persistent LI (PLI) in schizotypy and chronic SZ under conditions where normal participants fail to show LI. We hypothesized that Brain-Derived Neurotrophic Factor (BDNF)-Met genotype shifts LI toward the PLI pole. STUDY DESIGN: We investigated the role of BDNF-Val66Met polymorphism and neural activation in regions involved in LI in mice, and the interaction between the BDNF and CHL1, a gene associated with SZ. STUDY RESULTS: No LI differences occurred between BDNF-wild-type (WT) (Val/Val) and knock-in (KI) (Met/Met) mice after weak conditioning. Chronic stress or stronger conditioning disrupted LI in WT but not KI mice. Behavior correlated with activation in infralimbic and orbitofrontal cortices, and nucleus accumbens. Examination of LI in CHL1-KO mice revealed no LI with no Met alleles (BDNF-WTs), PLI in CHL1-WT mice with 1 Met allele (BDNF-HETs), and PLI in both CHL1-WTs and CHL1-KOs with 2 Met alleles (BDNF-KIs), suggesting a shift to LI persistence with the number of BDNF-Met alleles in the CHL1 model of acute SZ. CONCLUSIONS: Results support a role for BDNF polymorphisms in gene-gene and gene-environment interactions relevant to SZ. BDNF-Met allele may reduce expression of some acute SZ symptoms, and may increase expression of negative symptoms in individuals with chronic SZ. Evaluation of (screening for) SZ phenotypes associated with mutations at a particular locus (eg, CHL1), may be masked by strong effects at different loci (eg, BDNF).

mPFC catecholamines modulate attentional capture by appetitive distracters and attention to time in a peak-interval procedure in rats.

The behavioral and neural mechanisms by which distracters delay interval timing behavior are currently unclear. Distracters delay timing in a considerable dynamic range: Some distracters have no effect on timing ("run"), whereas others seem to "stop" timing; some distracters restart ("reset") the entire timing mechanisms at their offset, whereas others seem to capture attentional resources long after their termination ("over-reset"). While the run-reset range of delays is accounted for by the Time-Sharing Hypothesis (Buhusi, 2003, 2012), the behavioral and neural mechanisms of "over-resetting" are currently uncertain. We investigated the role of novelty (novel/familiar) and significance (consequential/inconsequential) in the time-delaying effect of distracters and the role of medial prefrontal cortex (mPFC) catecholamines by local infusion of norepinephrine-dopamine reuptake inhibitor (NDRI) nomifensine in a peak-interval (PI) procedure in rats. Results indicate differences in time delay between groups, suggesting a role for both novelty and significance: inconsequential, familiar distracters "stopped" timing, novel distracters "reset" timing, whereas appetitively conditioned distracters "over-reset" timing. mPFC infusion of nomifensine modulated attentional capture by appetitive distracters in a "U"-shaped fashion, reduced the delay after novel distracters, but had no effects after inconsequential, familiar distracters. These results were not due to nomifensine affecting either timing accuracy, precision, or peak response rate. Results may help elucidate the behavioral and physiological mechanisms underlying interval timing and attention to time and may contribute to developing new treatment strategies for disorders of attention. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Event-related correlates of evolving trust evaluations.

Accurate decisions about whether to trust someone are critical for adaptive social behavior. Previous research into trustworthiness decisions about face stimuli have focused on individuals. Here, decisions about groups of people are made cumulatively on the basis of sequences of faces. Participants chose to either increase or withdraw an initial investment in mock companies based on how trustworthy the company representatives (face stimuli) appeared. Companies were formed using participant trust ratings from the previous week, to create strong trustworthy, weak trustworthy, weak untrustworthy, and strong untrustworthy companies. Participants made faster, more accurate decisions for companies carrying stronger evidence (e.g., faces rated more extremely). Companies with more extreme ratings yielded faster decisions for untrustworthy than trustworthy companies, consistent with a negativity bias. Electrophysiological data revealed that amplitude of the P1 and P3 ERP components, linked to attentional processes, were largest for strong trustworthy faces. This suggests that evidence counter to bias draws special attention. In addition, the first face representing each company provoked larger amplitude P1, P3, and LPP than subsequent faces. This result suggests that when making social decisions about groups of people, the first person one meets receives the most attention.

Is the scalar property of interval timing preserved after hippocampus lesions?

Time perception is fundamental for decision-making, adaptation, and survival. In the peak-interval (PI) paradigm, one of the critical features of time perception is its scale invariance, i.e., the error in time estimation increases linearly with the to-be-timed interval. Brain lesions can profoundly alter time perception, but do they also change its scalar property? In particular, hippocampus (HPC) lesions affect the memory of the reinforced durations. Experiments found that ventral hippocampus (vHPC) lesions shift the perceived durations to longer values while dorsal hippocampus (dHPC) lesions produce opposite effects. Here we used our implementation of the Striatal Beat Frequency (SBFML) model with biophysically realistic Morris-Lecar (ML) model neurons and a topological map of HPC memory to predict analytically and verify numerically the effect of HPC lesions on scalar property. We found that scalar property still holds after both vHPC and dHPC lesions in our SBFML-HPC network simulation. Our numerical results show that PI durations are shifted in the correct direction and match the experimental results. In our simulations, the relative peak shift of the behavioral response curve is controlled by two factors: (1) the lesion size, and (2) the cellular-level memory variance of the temporal durations stored in the HPC. The coefficient of variance (CV) of the behavioral response curve remained constant over the tested durations of PI procedure, which suggests that scalar property is not affected by HPC lesions.

Blockade of Catecholamine Reuptake in the Prelimbic Cortex Decreases Top-down Attentional Control in Response to Novel, but Not Familiar Appetitive Distracters, within a Timing Paradigm.

Emotionally charged distracters delay timing behavior. Increasing catecholamine levels within the prelimbic cortex has beneficial effects on timing by decreasing the delay after aversive distracters. We examined whether increasing catecholamine levels within the prelimbic cortex also protects against the deleterious timing delays caused by novel distracters or by familiar appetitive distracters. Rats were trained in a peak-interval procedure and tested in trials with either a novel (unreinforced) distracter, a familiar appetitive (food-reinforced) distracter, or no distracter after being locally infused within the prelimbic cortex with catecholamine reuptake blocker nomifensine. Prelimbic infusion of nomifensine did not alter timing accuracy and precision. However, it increased the delay caused by novel distracters in an inverted-U dose-dependent manner, while being ineffective for appetitive distracters. Together with previous data, these results suggest that catecholaminergic modulation of prelimbic top-down attentional control of interval timing varies with distracter's valence: prelimbic catecholamines increase attentional control when presented with familiar aversive distracters, have no effect on familiar neutral or familiar appetitive distracters, and decrease it when presented with novel distracters. These findings detail complex interactions between catecholaminergic modulation of attention to timing and nontemporal properties of stimuli, which should be considered when developing therapeutic methods for attentional or affective disorders.

Episodic time in the brain: A new world order.

Recent findings from the laboratory of May-Britt and Edvard Moser (Tsao et al. in Nature 561, 57-62, 2018) suggest that episodic time is integrated from experience by a neural population in lateral entorhinal cortex that encodes events in a when-where-what trajectory at multiple time scales. While they provide a window into how the brain represents episodic memory, these findings also raise questions about whether this when-where-what trajectory truly reflects the temporal order of events, or whether one needs additional pieces of information to reconstruct temporal order, possibly using either associative information or evolutionary asymmetries built into biochemistry or neural circuits.

Neural Correlates of Interval Timing Deficits in Schizophrenia.

Previous research has shown that schizophrenia (SZ) patients exhibit impairments in interval timing. The cause of timing impairments in SZ remains unknown but may be explained by a dysfunction in the fronto-striatal circuits. Although the current literature includes extensive behavioral data on timing impairments, there is limited focus on the neural correlates of timing in SZ. The neuroimaging literature included in the current review reports hypoactivation in the dorsal-lateral prefrontal cortex (DLPFC), supplementary motor area (SMA) and the basal ganglia (BG). Timing deficits and deficits in attention and working memory (WM) in SZ are likely due to a dysfunction of dopamine (DA) and gamma-aminobutyric acid (GABA) neurotransmission in the cortico-striatal-thalamo-cortical circuits, which are highly implicated in executive functioning and motor preparation.

A Population-Based Model of the Temporal Memory in the Hippocampus.

Spatial and temporal dimensions are fundamental for orientation, adaptation, and survival of organisms. Hippocampus has been identified as the main neuroanatomical structure involved both in space and time perception and their internal representation. Dorsal hippocampus lesions showed a leftward shift (toward shorter durations) in peak-interval procedures, whereas ventral lesions shifted the peak time toward longer durations. We previously explained hippocampus lesion experimental findings by assuming a topological map model of the hippocampus with shorter durations memorized ventrally and longer durations more dorsal. Here we suggested a possible connection between the abstract topological maps model of the hippocampus that stored reinforcement times in a spatially ordered memory register and the "time cells" of the hippocampus. In this new model, the time cells provide a uniformly distributed time basis that covers the entire to-be-learned temporal duration. We hypothesized that the topological map of the hippocampus stores the weights that reflect the contribution of each time cell to the average temporal field that determines the behavioral response. The temporal distance between the to-be-learned criterion time and the time of the peak activity of each time cell provides the error signal that determines the corresponding weight correction. Long-term potentiation/depression could enhance/weaken the weights associated to the time cells that peak closer/farther to the criterion time. A coincidence detector mechanism, possibly under the control of the dopaminergic system, could be involved in our suggested error minimization and learning algorithm.

Inactivation of the Medial-Prefrontal Cortex Impairs Interval Timing Precision, but Not Timing Accuracy or Scalar Timing in a Peak-Interval Procedure in Rats.

Motor sequence learning, planning and execution of goal-directed behaviors, and decision making rely on accurate time estimation and production of durations in the seconds-to-minutes range. The pathways involved in planning and execution of goal-directed behaviors include cortico-striato-thalamo-cortical circuitry modulated by dopaminergic inputs. A critical feature of interval timing is its scalar property, by which the precision of timing is proportional to the timed duration. We examined the role of medial prefrontal cortex (mPFC) in timing by evaluating the effect of its reversible inactivation on timing accuracy, timing precision and scalar timing. Rats were trained to time two durations in a peak-interval (PI) procedure. Reversible mPFC inactivation using GABA agonist muscimol resulted in decreased timing precision, with no effect on timing accuracy and scalar timing. These results are partly at odds with studies suggesting that ramping prefrontal activity is crucial to timing but closely match simulations with the Striatal Beat Frequency (SBF) model proposing that timing is coded by the coincidental activation of striatal neurons by cortical inputs. Computer simulations indicate that in SBF, gradual inactivation of cortical inputs results in a gradual decrease in timing precision with preservation of timing accuracy and scalar timing. Further studies are needed to differentiate between timing models based on coincidence detection and timing models based on ramping mPFC activity, and clarify whether mPFC is specifically involved in timing, or more generally involved in attention, working memory, or response selection/inhibition.

Reducing impulsive choice: V. The role of timing in delay-exposure training.

Impulsive decision-making is common in addiction-related disorders, with some research suggesting it plays a causal role in their development. Therefore, reducing impulsive decision-making may prevent or reduce addiction-related behaviors. Recent research shows that prolonged experience with response-contingent delayed reward (delay exposure [DE] training) reduces impulsive choice in rats, but it is unclear what behavioral mechanisms underlie this effect. The present study evaluated whether improvements in interval timing mediate the effects of DE training on impulsive choice. Thirty-nine Long-Evans rats were randomly assigned to groups completing DE, immediacy-, or no-exposure training, followed by impulsive-choice and timing tasks (temporal bisection). Despite replicating the DE effect on impulsive choice, timing accuracy and precision were unaffected by DE training and unrelated to impulsive choice. The present findings did not replicate previous reports that timing precision and impulsive choice are related, which may be due to between-laboratory differences in impulsive choice tasks. Continued research to identify candidate behavioral mechanisms of DE training may assist in improving training efficacy and facilitating translational efforts.

Scalar timing in memory: A temporal map in the hippocampus.

Many essential tasks, such as decision making, rate calculation and planning, require accurate timing in the second to minute range. This process, known as interval timing, involves many cortical areas such as the prefrontal cortex, the striatum, and the hippocampus. Although the neurobiological origin and the mechanisms of interval timing are largely unknown, we have developed increasingly accurate mathematical and computational models that can mimic some properties of time perception. The accepted paradigm of temporal durations storage is that the objective elapsed time from the short-term memory is transferred to the reference memory using a multiplicative "memory translation constant" K*. It is believed that K* has a Gaussian distribution due to trial-related variabilities. To understand K* genesis, we hypothesized that the storage of temporal memories follows a topological map in the hippocampus, with longer durations stored towards dorsal hippocampus and shorter durations stored toward ventral hippocampus. We found that selective removal of memory cells in this topological map model shifts the peak-response time in a manner consistent with the current experimental data on the effect of hippocampal lesions on time perception. This opens new avenues for experimental testing of our topological map hypothesis. We found numerically that the relative shift is determined both by the lesion size and its location and we suggested a theoretical estimate for the memory translation constant K*.

Impaired Latent Inhibition in GDNF-Deficient Mice Exposed to Chronic Stress.

Increased reactivity to stress is maladaptive and linked to abnormal behaviors and psychopathology. Chronic unpredictable stress (CUS) alters catecholaminergic neurotransmission and remodels neuronal circuits involved in learning, attention and decision making. Glial-derived neurotrophic factor (GDNF) is essential for the physiology and survival of dopaminergic neurons in substantia nigra and of noradrenergic neurons in the locus coeruleus. Up-regulation of GDNF expression during stress is linked to resilience; on the other hand, the inability to up-regulate GDNF in response to stress, as a result of either genetic or epigenetic modifications, induces behavioral alterations. For example, GDNF-deficient mice exposed to chronic stress exhibit alterations of executive function, such as increased temporal discounting. Here we investigated the effects of CUS on latent inhibition (LI), a measure of selective attention and learning, in GDNF-heterozygous (HET) mice and their wild-type (WT) littermate controls. No differences in LI were found between GDNF HET and WT mice under baseline experimental conditions. However, following CUS, GDNF-deficient mice failed to express LI. Moreover, stressed GDNF-HET mice, but not their WT controls, showed decreased neuronal activation (number of c-Fos positive neurons) in the nucleus accumbens shell and increased activation in the nucleus accumbens core, both key regions in the expression of LI. Our results add LI to the list of behaviors affected by chronic stress and support a role for GDNF deficits in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders.

Increased Hippocampal ProBDNF Contributes to Memory Impairments in Aged Mice.

Memory decline during aging or accompanying neurodegenerative diseases, represents a major health problem. Neurotrophins have long been considered relevant to the mechanisms of aging-associated cognitive decline and neurodegeneration. Mature Brain-Derived Neurotrophic Factor (BDNF) and its precursor (proBDNF) can both be secreted in response to neuronal activity and exert opposing effects on neuronal physiology and plasticity. In this study, biochemical analyses revealed that increased levels of proBDNF are present in the aged mouse hippocampus relative to young and that the level of hippocampal proBDNF inversely correlates with the ability to perform in a spatial memory task, the water radial arm maze (WRAM). To ascertain the role of increased proBDNF levels on hippocampal function and memory we performed infusions of proBDNF into the CA1 region of the dorsal hippocampus in male mice trained in the WRAM paradigm: In well-performing aged mice, intra-hippocampal proBDNF infusions resulted in a progressive and significant impairment of memory performance. This impairment was associated with increased p-cofilin levels, an important regulator of dendritic spines and synapse physiology. On the other hand, in poor performers, intra-hippocampal infusions of TAT-Pep5, a peptide which blocks the interaction between the p75 Neurotrophin Receptor (p75NTR) and RhoGDI, significantly improved learning and memory, while saline infusions had no effect. Our results support a role for proBDNF and its receptor p75NTR in aging-related memory impairments.

Chronic mild stress impairs latent inhibition and induces region-specific neural activation in CHL1-deficient mice, a mouse model of schizophrenia.

Schizophrenia is a neurodevelopmental disorder characterized by abnormal processing of information and attentional deficits. Schizophrenia has a high genetic component but is precipitated by environmental factors, as proposed by the 'two-hit' theory of schizophrenia. Here we compared latent inhibition as a measure of learning and attention, in CHL1-deficient mice, an animal model of schizophrenia, and their wild-type littermates, under no-stress and chronic mild stress conditions. All unstressed mice as well as the stressed wild-type mice showed latent inhibition. In contrast, CHL1-deficient mice did not show latent inhibition after exposure to chronic stress. Differences in neuronal activation (c-Fos-positive cell counts) were noted in brain regions associated with latent inhibition: Neuronal activation in the prelimbic/infralimbic cortices and the nucleus accumbens shell was affected solely by stress. Neuronal activation in basolateral amygdala and ventral hippocampus was affected independently by stress and genotype. Most importantly, neural activation in nucleus accumbens core was affected by the interaction between stress and genotype. These results provide strong support for a 'two-hit' (genes x environment) effect on latent inhibition in CHL1-deficient mice, and identify CHL1-deficient mice as a model of schizophrenia-like learning and attention impairments.