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).

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*.

Nerve growth factor metabolic dysfunction in Down's syndrome brains.

Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down's syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome.

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.

EphB regulates L1 phosphorylation during retinocollicular mapping.

Interaction of the cell adhesion molecule L1 with the cytoskeletal adaptor ankyrin is essential for topographic mapping of retinal ganglion cell (RGC) axons to synaptic targets in the superior colliculus (SC). Mice mutated in the L1 ankyrin-binding motif (FIGQY(1229)H) display abnormal mapping of RGC axons along the mediolateral axis of the SC, resembling mouse mutant phenotypes in EphB receptor tyrosine kinases. To investigate whether L1 functionally interacts with EphBs, we investigated the role of EphB kinases in phosphorylating L1 using a phospho-specific antibody to the tyrosine phosphorylated FIGQY(1229) motif. EphB2, but not an EphB2 kinase dead mutant, induced tyrosine phosphorylation of L1 at FIGQY(1229) and perturbed ankyrin recruitment to the membrane in L1-transfected HEK293 cells. Src family kinases mediated L1 phosphorylation at FIGQY(1229) by EphB2. Other EphB receptors that regulate medial-lateral retinocollicular mapping, EphB1 and EphB3, also mediated phosphorylation of L1 at FIGQY(1229). Tyrosine(1176) in the cytoplasmic domain of L1, which regulates AP2/clathrin-mediated endocytosis and axonal trafficking, was not phosphorylated by EphB2. Accordingly mutation of Tyr(1176) to Ala in L1-Y(1176)A knock-in mice resulted in normal retinocollicular mapping of ventral RGC axons. Immunostaining of the mouse SC during retinotopic mapping showed that L1 colocalized with phospho-FIGQY in RGC axons in retinorecipient layers. Immunoblotting of SC lysates confirmed that L1 was phosphorylated at FIGQY(1229) in wild type but not L1-FIGQY(1229)H (L1Y(1229)H) mutant SC, and that L1 phosphorylation was decreased in the EphB2/B3 mutant SC. Inhibition of ankyrin binding in L1Y(1229)H mutant RGCs resulted in increased neurite outgrowth compared to WT RGCs in retinal explant cultures, suggesting that L1-ankyrin binding serves to constrain RGC axon growth. These findings are consistent with a model in which EphB kinases phosphorylate L1 at FIGQY(1229) in retinal axons to modulate L1-ankyrin binding important for mediolateral retinocollicular topography.

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).

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.

RPE65 is present in human green/red cones and promotes photopigment regeneration in an in vitro cone cell model.

RPE65 is an abundantly expressed protein within the retinal pigment epithelium (RPE) of the eye that is required for retinoid metabolism to support vision. Its genetic mutations are linked to the congenital disease Leber congenital amaurosis Type 2 (LCA2) characterized by the early onset of central vision loss. Current gene therapy trials have targeted restoration of functional RPE65 within the RPE of these patients with some success. Recent data show that RPE65 is also present within mouse cones to promote function. In this study, we evaluated the presence of RPE65 in human cones and investigated its potential mechanism for supporting cone function in the 661W cone cell line. We found that RPE65 was selectively expressed in human green/red cones but absent from blue cones and mediated ester hydrolysis for photopigment synthesis in vitro. These data suggest that cone RPE65 supports human diurnal vision, potentially enhancing our strategies for treating LCA2.

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).

ALCAM regulates mediolateral retinotopic mapping in the superior colliculus.

ALCAM [activated leukocyte cell adhesion molecule (BEN/SC-1/DM-GRASP)] is a transmembrane recognition molecule of the Ig superfamily (IgSF) containing five Ig domains (two V-type, three C2-type). Although broadly expressed in the nervous and immune systems, few of its developmental functions have been elucidated. Because ALCAM has been suggested to interact with the IgSF adhesion molecule L1, a determinant of retinocollicular mapping, we hypothesized that ALCAM might direct topographic targeting to the superior colliculus (SC) by serving as a substrate within the SC for L1 on incoming retinal ganglion cell (RGC) axons. ALCAM was expressed in the SC during RGC axon targeting and on RGC axons as they formed the optic nerve; however, it was downregulated distally on RGC axons as they entered the SC. Axon tracing with DiI revealed pronounced mistargeting of RGC axons from the temporal retina half of ALCAM null mice to abnormally lateral sites in the contralateral SC, in which these axons formed multiple ectopic termination zones. ALCAM null mutant axons were specifically compromised in medial orientation of interstitial branches, which is known to require the ankyrin binding function of L1. As a substrate, ALCAM-Fc protein promoted L1-dependent attachment of acutely dissociated retinal cells and an L1-expressing, ALCAM-negative cell line, consistent with an ALCAM-L1 heterophilic molecular interaction. Together, these results suggest a model in which ALCAM in the SC interacts with L1 on RGC axons to promote medial extension of RGC axon branches important for mediolateral axon targeting in the formation of retinocollicular maps.

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.

Interaction Between Physical Activity and Genes Related to Neurotrophin Signaling in Late-Life Cognitive Performance: The Cache County Study.

Research indicates that lifestyle and genetic factors influence the course of cognitive impairment in aging, but their interactions have not been well-examined. This study examined the relationship between physical activity and genotypes related to brain-derived neurotrophic factor (BDNF) in predicting cognitive performance in a sample of older adults with up to 12 years of follow-up. Physical activity levels (sedentary, light, and moderate/vigorous) were determined for the sample of 3,591 participants (57% female) without dementia. The genotypes examined included BDNF gene single nucleotide polymorphisms (SNPs) (rs6265 and rs56164415) and receptor gene SNPs (NTRK2 rs2289656 and NGFR rs2072446). Cognition was assessed triennially using the Modified Mini-Mental State Exam. Unadjusted linear mixed models indicated that sedentary (ß = -5.05) and light (ß = -2.41) groups performed worse than moderate-vigorous (p < .001). Addition of interaction effects showed significant differences in rate of decline between activity levels, particularly among males (p = .006). A three-way interaction with sex, NGFR SNP rs2072446, and physical activity suggested that the C/C allele was associated with better cognitive performance among males engaging in light activity only (p = .004). Physical activity and sex, but not BDNF-related SNPs, predicted rate of cognitive decline in older adults, while NGFR rs2072446 may modify main effects.

L1 interaction with ankyrin regulates mediolateral topography in the retinocollicular projection.

Dynamic modulation of adhesion provided by anchorage of axonal receptors with the cytoskeleton contributes to attractant or repellent responses that guide axons to topographic targets in the brain. The neural cell adhesion molecule L1 engages the spectrin-actin cytoskeleton through reversible linkage of its cytoplasmic domain to ankyrin. To investigate a role for L1 association with the cytoskeleton in topographic guidance of retinal axons to the superior colliculus, a novel mouse strain was generated by genetic knock-in that expresses an L1 point mutation (Tyr1229His) abolishing ankyrin binding. Axon tracing revealed a striking mistargeting of mutant ganglion cell axons from the ventral retina, which express high levels of ephrinB receptors, to abnormally lateral sites in the contralateral superior colliculus, where they formed multiple ectopic arborizations. These axons were compromised in extending interstitial branches in the medial direction, a normal response to the high medial to low lateral SC gradient of ephrinB1. Furthermore, ventral but not dorsal L1(Y1229H) retinal cells were impaired for ephrinB1-stimulated adhesion through beta1 integrins in culture. The retinocollicular phenotype of the L1(Tyr1229His) mutant provides the first evidence that L1 regulates topographic mapping of retinal axons through adhesion mediated by linkage to the actin cytoskeleton and functional interaction with the ephrinB/EphB targeting system.

Lifetime estrogen exposure and cognition in late life: the Cache County Study.

OBJECTIVE: Prevalence of Alzheimer's disease (AD) is higher for women, possibly influenced by sex-dependent effects of the estrogen. We examined the association between estrogen and cognitive decline in over 2,000 older adult women in a 12-year population-based study in Cache County, Utah. METHODS: The baseline sample included 2,114 women (mean age = 74.94 y, SD = 6.71) who were dementia-free at baseline and completed a women's health questionnaire, asking questions regarding reproductive history and hormone therapy (HT). Endogenous estrogen exposure (EEE) was calculated taking the reproductive window (age at menarche to age at menopause), adjusted for pregnancy and breastfeeding. HT variables included duration of use, HT type (unopposed; opposed), and time of HT initiation. A modified version of the Mini-Mental State Examination (3MS) was administered at four triennial waves to assess cognitive status. Linear mixed-effects models examined the relationship between estrogen exposure and 3MS score over time. RESULTS: EEE was positively associated with cognitive status (ß = 0.03, P = 0.054). In addition, longer duration of HT use was positively associated with cognitive status (ß = 0.02, P = 0.046) and interacted with age; older women had greater benefit compared with younger women. The timing of HT initiation was significantly associated with 3MS (ß = 0.55, P = 0.048), with higher scores for women who initiated HT within 5 years of menopause compared with those initiating HT 6-or-more years later. CONCLUSIONS: Our results suggest that longer EEE and HT use, especially in older women, are associated with higher cognitive status in late life.

CHL1 promotes Sema3A-induced growth cone collapse and neurite elaboration through a motif required for recruitment of ERM proteins to the plasma membrane.

Close homolog of L1 (CHL1) is a transmembrane cell adhesion molecule with unique developmental functions in cortical neuronal positioning and dendritic projection within the L1 family, as well as shared functions in promotion of integrin-dependent neurite outgrowth and semaphorin3A (Sema3A)-mediated axon repulsion. The molecular mechanisms by which CHL1 mediates these diverse functions are obscure. Here it is demonstrated using a cytofluorescence assay that CHL1 is able to recruit ezrin, a member of the ezrin-radixin-moesin (ERM) family of filamentous actin binding proteins to the plasma membrane, and that this requires a membrane-proximal motif (RGGKYSV) in the CHL1 cytoplasmic domain. This sequence in CHL1 is shown to have novel functions necessary for Sema3A-induced growth cone collapse and CHL1-dependent neurite outgrowth and branching in cortical embryonic neurons. In addition, stimulation of haptotactic cell migration and cellular adhesion to fibronectin by CHL1 depends on the CHL1/ERM recruitment motif. These findings suggest that a direct or indirect interaction between CHL1 and ERM proteins mediates Sema3A-induced growth cone collapse as well as neurite outgrowth and branching, which are essential determinants of axon guidance and connectivity in cortical development.

The nigrostriatal dopamine system of aging GFRalpha-1 heterozygous mice: neurochemistry, morphology and behavior.

Given the established importance of glial cell line-derived neurotrophic factor (GDNF) in maintaining dopaminergic neurotransmitter systems, the nigrostriatal system and associated behaviors of mice with genetic reduction of its high-affinity receptor, GDNF receptor (GFR)alpha-1 (GFRalpha-1(+/-)), were compared with wild-type controls. Motor activity and the stimulatory effects of a dopamine (DA) D1 receptor agonist (SKF 82958) were assessed longitudinally at 8 and 18 months of age. Monoamine concentrations and dopaminergic nerve terminals in the striatum and the number of dopaminergic neurons in the substantia nigra (SN) were assessed. The results support the importance of GFRalpha-1 in maintaining normal function of the nigrostriatal dopaminergic system, with deficits being observed for GFRalpha-1(+/-) mice at both ages. Motor activity was lower and the stimulatory effects of the DA agonist were enhanced for the older GFRalpha-1(+/-) mice. DA in the striatum was reduced in the GFRalpha-1(+/-) mice at both ages, and tyrosine hydroxylase-positive cell numbers in the SN were reduced most substantially in the older GFRalpha-1(+/-) mice. The combined behavioral, pharmacological probe, neurochemical and morphological measures provide evidence of abnormalities in GFRalpha-1(+/-) mice that are indicative of an exacerbated aging-related decline in dopaminergic system function. The noted deficiencies, in turn, suggest that GFRalpha-1 is necessary for GDNF to maintain normal function of the nigrostriatal dopaminergic system. Although the precise mechanism(s) for the aging-related changes in the dopaminergic system remain to be established, the present study clearly establishes that genetic reductions in GFRalpha-1 can contribute to the degenerative changes observed in this system during the aging process.

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.