Circadian neurogenetics and its implications in neurophysiology, behavior, and chronomedicine.

The circadian rhythm affects multiple physiological processes, and disruption of the circadian system can be involved in a range of disease-related pathways. The genetic underpinnings of the circadian rhythm have been well-studied in model organisms. Significant progress has been made in understanding how clock genes affect the physiological functions of the nervous system. In addition, circadian timing is becoming a key factor in improving drug efficacy and reducing drug toxicity. The circadian biology of the target cell determines how the organ responds to the drug at a specific time of day, thus regulating pharmacodynamics. The current review brings together recent advances that have begun to unravel the molecular mechanisms of how the circadian clock affects neurophysiological and behavioral processes associated with human brain diseases. We start with a brief description of how the ubiquitous circadian rhythms are regulated at the genetic, cellular, and neural circuit levels, based on knowledge derived from extensive research on model organisms. We then summarize the latest findings from genetic studies of human brain disorders, focusing on the role of human clock gene variants in these diseases. Lastly, we discuss the impact of common dietary factors and medications on human circadian rhythms and advocate for a broader application of the concept of chronomedicine.

The 5-HT1A receptor agonist 8-OH-DPAT modulates motor/exploratory activity, recognition memory and dopamine transporter binding in the dorsal and ventral striatum.

In the present studies, we assessed the effect of the 5-HT1A receptor (R) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on motor and exploratory behaviors, object and place recognition and dopamine transporter (DAT) and serotonin transporter (SERT) binding in the rat brain. In Experiment I, motor/exploratory behaviors were assessed in an open field after injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle for 30 min without previous habituation to the open field. In Experiment II, rats underwent a 5-min exploration trial in an open field with two identical objects. After injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle, rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Subsequently, N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]FP-CIT; 11 ± 4 MBq) was injected into the tail vein. Regional radioactivity accumulations were determined post mortem with a well counter. In both experiments, 8-OH-DPAT dose-dependently increased ambulation and exploratory head-shoulder motility, whereas rearing was dose-dependently decreased. In the test rial of Experiment II, there were no effects of 8-OH-DPAT on overall activity, sitting and grooming. 8-OH-DPAT dose-dependently impaired recognition of object and place. 8-OH-DPAT (3 mg/kg) increased DAT binding in the dorsal striatum relative to both vehicle and 0.1 mg/kg 8-OH-DPAT. Furthermore, in the ventral striatum, DAT binding was decreased after 3 mg/kg 8-OH-DPAT relative to vehicle. Findings indicate that motor/exploratory behaviors, memory for object and place and regional dopamine function may be modulated by the 5-HT1AR. Since, after 8-OH-DPAT, rats exhibited more horizontal and less (exploratory) vertical motor activity, while overall activity was not different between groups, it may be inferred, that the observed impairment of object recognition was not related to a decrease of motor activity as such, but to a decrease of intrinsic motivation, attention and/or awareness, which are relevant accessories of learning. Furthermore, the present findings on 8-OH-DPAT action indicate associations not only between motor/exploratory behavior and the recognition of object and place but also between the respective parameters and the levels of available DA in dorsal and ventral striatum.

Social memory deficit caused by dysregulation of the cerebellar vermis.

Social recognition memory (SRM) is a key determinant of social interactions. While the cerebellum emerges as an important region for social behavior, how cerebellar activity affects social functions remains unclear. We selectively increased the excitability of molecular layer interneurons (MLIs) to suppress Purkinje cell firing in the mouse cerebellar vermis. Chemogenetic perturbation of MLIs impaired SRM without affecting sociability, anxiety levels, motor coordination or object recognition. Optogenetic interference of MLIs during distinct phases of a social recognition test revealed the cerebellar engagement in the retrieval, but not encoding, of social information. c-Fos mapping after the social recognition test showed that cerebellar manipulation decreased brain-wide interregional correlations and altered network structure from medial prefrontal cortex and hippocampus-centered to amygdala-centered modules. Anatomical tracing demonstrated hierarchical projections from the central cerebellum to the social brain network integrating amygdalar connections. Our findings suggest that the cerebellum organizes the neural matrix necessary for SRM.

Probing the nature of episodic memory in rodents.

Episodic memory (EM) specifies the experience of retrieving information of an event at the place and time of occurrence. Whether non-human animals are capable of EM remains debated, whereas evidence suggests that they have a memory system akin to EM. We here trace the development of various behavioral paradigms designed to study EM in non-human animals, in particular the rat. We provide an in-depth description of the available behavioral tests which combine three spontaneous object exploration paradigms, namely novel object preference (for measuring memory for "what"), novel location preference (for measuring memory for "where") and temporal order memory (memory for "when"), into a single trial to gauge a memory akin to EM. Most important, we describe a variation of such a test in which each memory component interacts with the others, demonstrating an integration of diverse mnemonic information. We discuss why a behavioral model of EM must be able to assess the ability to integrate "what", "where" and "when" information into a single experience. We attempt an interpretation of the various tests and review the studies that have applied them in areas such as pharmacology, neuroanatomy, circuit analysis, and sleep. Finally, we anticipate future directions in the search for neural mechanisms of EM in the rat and outline model experiments and methodologies in this pursuit.

Neuronal circuitry for recognition memory of object and place in rodent models.

Rats and mice are used for studying neuronal circuits underlying recognition memory due to their ability to spontaneously remember the occurrence of an object, its place and an association of the object and place in a particular environment. A joint employment of lesions, pharmacological interventions, optogenetics and chemogenetics is constantly expanding our knowledge of the neural basis for recognition memory of object, place, and their association. In this review, we summarize current studies on recognition memory in rodents with a focus on the novel object preference, novel location preference and object-in-place paradigms. The evidence suggests that the medial prefrontal cortex- and hippocampus-connected circuits contribute to recognition memory for object and place. Under certain conditions, the striatum, medial septum, amygdala, locus coeruleus and cerebellum are also involved. We propose that the neuronal circuitry for recognition memory of object and place is hierarchically connected and constructed by different cortical (perirhinal, entorhinal and retrosplenial cortices), thalamic (nucleus reuniens, mediodorsal and anterior thalamic nuclei) and primeval (hypothalamus and interpeduncular nucleus) modules interacting with the medial prefrontal cortex and hippocampus.

Disrupted-in-schizophrenia 1 Protein Misassembly Impairs Cognitive Flexibility and Social Behaviors in a Transgenic Rat Model.

Alterations in cognitive functions, social behaviors and stress reactions are commonly diagnosed in chronic mental illnesses (CMI). Animal models expressing mutant genes associated to CMI represent either rare mutations or those contributing only minimally to genetic risk. Non-genetic causes of CMI can be modeled by disturbing downstream signaling pathways, for example by inducing protein misassembly or aggregation. The Disrupted-in-Schizophrenia 1 (DISC1) gene was identified to be disrupted and thereby haploinsufficient in a large pedigree where it was associated with CMI. In a subset of CMI patients, the DISC1 protein misassembles to an insoluble protein. This has been modeled in a rat (tgDISC1 rat) where the full-length, non mutant human transgene was overexpressed and cognitive impairments were observed. Here, we investigated the scope of effects of DISC1 protein misassembly by investigating spatial memory, social behavior and stress resilience. In water maze tasks, the tgDISC1 rats showed intact spatial learning and memory, but were deficient in flexible adaptation to spatial reversal learning compared to littermate controls. They also displayed less social interaction. Additionally, there was a trend towards increased corticosterone levels after restraint stress in the tgDISC1 rats. Our findings suggest that DISC1 protein misassembly leads to disturbances of cognitive flexibility and social behaviors, and might also be involved in stress sensitization. Since the observed behavioral features resemble symptoms of CMI, the tgDISC1 rat may be a valuable model for the investigation of cognitive, social and - possibly - also stress-related symptoms of major mental illnesses.

Disruption of Circadian Rhythms by Ambient Light during Neurodevelopment Leads to Autistic-like Molecular and Behavioral Alterations in Adult Mice.

Although circadian rhythms are thought to be essential for maintaining body health, the effects of chronic circadian disruption during neurodevelopment remain elusive. Here, using the "Short Day" (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was applied from embryonic day 1 to postnatal day 42, we investigated the molecular and behavioral changes after circadian disruption in mice. Adult SD mice fully entrained to the 8 h/8 h LD cycle, and the circadian oscillations of the clock proteins, PERIOD1 and PERIOD2, were disrupted in the suprachiasmatic nucleus and the hippocampus of these mice. By RNA-seq widespread changes were identified in the hippocampal transcriptome, which are functionally associated with neurodevelopment, translational control, and autism. By western blotting and immunostaining hyperactivation of the mTOR and MAPK signaling pathways and enhanced global protein synthesis were found in the hippocampi of SD mice. Electrophysiological recording uncovered enhanced excitatory, but attenuated inhibitory, synaptic transmission in the hippocampal CA1 pyramidal neurons. These functional changes at synapses were corroborated by the immature morphology of the dendritic spines in these neurons. Lastly, autistic-like animal behavioral changes, including impaired social interaction and communication, increased repetitive behaviors, and impaired novel object recognition and location memory, were found in SD mice. Together, these results demonstrate molecular, cellular, and behavioral changes in SD mice, all of which resemble autistic-like phenotypes caused by circadian rhythm disruption. The findings highlight a critical role for circadian rhythms in neurodevelopment.

Acute intranasal dopamine application counteracts the reversal learning deficit of spontaneously hypertensive rats in an attentional set-shifting task.

RATIONALE: Studies on the attention-deficit/hyperactivity disorder (ADHD) have concluded that the disorder might be caused by a deficit in the inhibitory control of executive functions because of dopamine hypofunction. Recently, the intranasal route has emerged as an effective alternative means for sending dopamine directly to the brain. However, whether the treatment can ameliorate the deficits of inhibitory control in ADHD remains unknown. OBJECTIVES: Investigating the effects of acute intranasal dopamine (IN-DA) on the inhibitory control of executive functions of an ADHD rodent model. METHODS: We trained an animal model of ADHD, the spontaneously hypertensive rat (SHR), and Wistar rats as controls, in an attentional set-shifting task (ASST) in which dopamine (0.15 mg/kg, 0.3 mg/kg, or vehicle) was intranasally administered before the final test. RESULTS: IN-DA application dose-dependently improved the performance and reduced errors of SHR in the initial reversal learning. The effect size was comparable to that of a peripheral injection of 0.6 mg/kg methylphenidate. In control Wistar rats, the highest dose of intranasal dopamine (0.3 mg/kg) induced deficits in the reversal learning of extradimensional discriminations. CONCLUSIONS: The findings suggest that the IN-DA treatment has potential for use in the treatment of ADHD; however, caution must be exercised when determining the dosage to be administered, because too much dopamine may have negative effects.

Functional Convergence of Motor and Social Processes in Lobule IV/V of the Mouse Cerebellum.

Topographic organization of the cerebellum is largely segregated into the anterior and posterior lobes that represent its "motor" and "non-motor" functions, respectively. Although patients with damage to the anterior cerebellum often exhibit motor deficits, it remains unclear whether and how such an injury affects cognitive and social behaviors. To address this, we perturbed the activity of major anterior lobule IV/V in mice by either neurotoxic lesion or chemogenetic excitation of Purkinje cells in the cerebellar cortex. We found that both of the manipulations impaired motor coordination, but not general locomotion or anxiety-related behavior. The lesioned animals showed memory deficits in object recognition and social-associative recognition tests, which were confounded by a lack of exploration. Chemogenetic excitation of Purkinje cells disrupted the animals' social approach in a less-preferred context and social memory, without affecting their overall exploration and object-based memory. In a free social interaction test, the two groups exhibited less interaction with a stranger conspecific. Subsequent c-Fos imaging indicated that decreased neuronal activities in the medial prefrontal cortex, hippocampal dentate gyrus, parahippocampal cortices, and basolateral amygdala, as well as disorganized modular structures of the brain networks might underlie the reduced social interaction. These findings suggest that the anterior cerebellum plays an intricate role in processing motor, cognitive, and social functions.

Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism.

The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whether DA can be utilized as a potential therapeutic agent for ASD. To this end, we employed a phenotypic and a genetic ASD model, i.e., Black and Tan BRachyury T+Itpr3tf/J (BTBR) mice and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction in the TH expression in the substantia nigra, ventral tegmental area and dorsal striatum of BTBR mice, as compared to C57BL/6 J wild-type ones. In contrast, Fmr1-KO animals did not show such an alteration but displayed abnormal morphology of TH-positive axons in the striatum with higher "complexity" and lower "texture". Both strains exhibited decreased expression of striatal dopamine transporter (DAT) and increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1, a label for glutamatergic terminals) and TH signals, while GABAergic neurons quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration of DA rescued the deficits in non-selective attention, object-based attention and social approaching of BTBR mice, likely by enhancing the level of TH in the striatum. Application of intranasal DA to Fmr1-KO animals alleviated their impairment of social novelty, in association with reduced striatal TH protein. These results suggest that although the DA system is modified differently in the two ASD models, intranasal treatment with DA effectively rectifies their behavioral phenotypes, which may present a promising therapy for diverse types of ASD.

The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties.

Rats and mice have been demonstrated to show episodic-like memory, a prototype of episodic memory, as defined by an integrated memory of the experience of an object or event, in a particular place and time. Such memory can be assessed via the use of spontaneous object exploration paradigms, variably designed to measure memory for object, place, temporal order and object-location inter-relationships. We review the methodological properties of these tests, the neurobiology about time and discuss the evidence for the involvement of the medial prefrontal cortex (mPFC), entorhinal cortex (EC) and hippocampus, with respect to their anatomy, neurotransmitter systems and functional circuits. The systematic analysis suggests that a specific circuit between the mPFC, lateral EC and hippocampus encodes the information for event, place and time of occurrence into the complex episodic-like memory, as a top-down regulation from the mPFC onto the hippocampus. This circuit can be distinguished from the neuronal component memory systems for processing the individual information of object, time and place.

Targeting inhibitory cerebellar circuitry to alleviate behavioral deficits in a mouse model for studying idiopathic autism.

Autism spectrum disorder (ASD) encompasses wide-ranging neuropsychiatric symptoms with unclear etiology. Although the cerebellum is a key region implicated in ASD, it remains elusive how the cerebellar circuitry is altered and whether the cerebellum can serve as a therapeutic target to rectify the phenotype of idiopathic ASD with polygenic abnormalities. Using a syndromic ASD model, e.g., Black and Tan BRachyury T+Itpr3tf/J (BTBR) mice, we revealed that increased excitability of presynaptic interneurons (INs) and decreased intrinsic excitability of postsynaptic Purkinje neurons (PNs) resulted in low PN firing rates in the cerebellum. Knowing that downregulation of Kv1.2 potassium channel in the IN nerve terminals likely augmented their excitability and GABA release, we applied a positive Kv1.2 modulator to mitigate the presynaptic over-inhibition and social impairment of BTBR mice. Selective restoration of the PN activity by a new chemogenetic approach alleviated core ASD-like behaviors of the BTBR strain. These findings highlight complex mechanisms converging onto the cerebellar dysfunction in the phenotypic model and provide effective strategies for potential therapies of ASD.

Identification of a molecular locus for normalizing dysregulated GABA release from interneurons in the Fragile X brain.

Principal neurons encode information by varying their firing rate and patterns precisely fine-tuned through GABAergic interneurons. Dysregulation of inhibition can lead to neuropsychiatric disorders, yet little is known about the molecular basis underlying inhibitory control. Here, we find that excessive GABA release from basket cells (BCs) attenuates the firing frequency of Purkinje neurons (PNs) in the cerebellum of Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mice, a model of Fragile X Syndrome (FXS) with abrogated expression of the Fragile X Mental Retardation Protein (FMRP). This over-inhibition originates from increased excitability and Ca2+ transients in the presynaptic terminals, where Kv1.2 potassium channels are downregulated. By paired patch-clamp recordings, we further demonstrate that acutely introducing an N-terminal fragment of FMRP into BCs normalizes GABA release in the Fmr1-KO synapses. Conversely, direct injection of an inhibitory FMRP antibody into BCs, or membrane depolarization of BCs, enhances GABA release in the wild type synapses, leading to abnormal inhibitory transmission comparable to the Fmr1-KO neurons. We discover that the N-terminus of FMRP directly binds to a phosphorylated serine motif on the C-terminus of Kv1.2; and that loss of this interaction in BCs exaggerates GABA release, compromising the firing activity of PNs and thus the output from the cerebellar circuitry. An allosteric Kv1.2 agonist, docosahexaenoic acid, rectifies the dysregulated inhibition in vitro as well as acoustic startle reflex and social interaction in vivo of the Fmr1-KO mice. Our results unravel a novel molecular locus for targeted intervention of FXS and perhaps autism.

Timing constraints of action potential evoked Ca2+ current and transmitter release at a central nerve terminal.

The waveform of presynaptic action potentials (APs) regulates the magnitude of Ca2+ currents (ICa) and neurotransmitter release. However, how APs control the timing of synaptic transmission remains unclear. Using the calyx of Held synapse, we find that Na+ and K+ channels affect the timing by changing the AP waveform. Specifically, the onset of ICa depends on the repolarization but not depolarization rate of APs, being near the end of repolarization phase for narrow APs and advancing to the early repolarization phase for wide APs. Increasing AP amplitude has little effect on the activation but delays the peak time of ICa. Raising extracellular Ca2+ concentration increases the amplitude of ICa yet does not alter their onset timing. Developmental shortening of APs ensures ICa as a tail current and faithful synaptic delay, which is particularly important at the physiological temperature (35 °C) as ICa evoked by broad pseudo-APs can occur in the depolarization phase. The early onset of ICa is more prominent at 35 °C than at 22 °C, likely resulting from a temperature-dependent shift in the activation threshold and accelerated gating kinetics of Ca2+ channels. These results suggest that the timing of Ca2+ influx depends on the AP waveform dictated by voltage-gated channels and temperature.

Anxiogenic-like behavior and deficient attention/working memory in rats expressing the human DISC1 gene.

In humans, mutations in the Disrupted-in-schizophrenia 1 (DISC1) gene have been related to psychiatric disorders, including symptoms of abnormal cognitive and emotional behaviors. In our previous studies, overexpression of the human DISC1 gene in rats resulted in schizophrenia-like phenotypes showing deficits in motor learning, impaired cognitive function and dysfunctions of the dopamine system. Here we asked, whether the DISC1 overexpression affects locomotor activity in the open field (OF), anxiety in the elevated plus-maze (EPM), depression-related behavior in the forced swim test (FST), and attention-like/short-term working-memory in the spontaneous alternation behavior (SAB) in the T-maze in transgenic DISC1 (tgDISC1) rats and littermate controls (WT). TgDISC1 rats showed enhanced anxiety behavior in the EPM and an impairment in attention-like/short-term working-memory in the SAB. However, tgDISC1 animals showed no locomotor impairments or depression-like behavior in the OF and FST. These results suggest that DISC1 overexpression leads to higher anxiety level and an attention-like/working-memory deficit. These findings may expand the causal role of DISC1 in its contribution to multiple symptom dimensions of psychiatric disorders.

Aß dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease.

We examined behaviors and neurotransmitter levels in the tgDimer mouse, a model for early Alzheimer's disease, that expresses exclusively soluble amyloid beta (Aß) dimers and is devoid of Aß plaques, astrogliosis, and neuroinflammation. Seven-month-old mice were subjected to tests of motor activity, attention, anxiety, habituation learning, working memory, and depression-related behaviors. They were impaired in nonselective attention and motor learning and showed anxiety- and despair-related behaviors. In 7- and 12-month-old mice, levels of acetylcholine, dopamine, and serotonin were measured in neostriatum, ventral striatum, prefrontal cortex, hippocampus, amygdala, and entorhinal cortex by high-performance liquid chromatography. The tgDimer mice had lower serotonin turnover rates in hippocampus, ventral striatum, and amygdala relative to wild type controls. The aged tgDimer mice had less hippocampal acetylcholine than adult tgDimers. Stress-test results, based on corticosterone levels, indicated an intact hypothalamus-pituitary-adrenal axis in 12-month-old mice. Since neither Aß plaques nor astrogliosis or neuroinflammation was responsible for these phenotypes, we conclude that Aß dimers contribute to neurotransmitter dysfunction and behavioral impairments, characteristic for the early stages of Alzheimer's disease.

Behavioral assessments of BTBR T+Itpr3tf/J mice by tests of object attention and elevated open platform: Implications for an animal model of psychiatric comorbidity in autism.

Autism spectrum disorders (ASD) are diagnosed based on the behavioral criteria of impaired social interaction, defective communication and repetitive behaviors. Psychiatric comorbidities, such as anxiety and intellectual disability, are commonly present in ASD. The BTBR T+ Itpr3tf/J (BTBR) mice display a range of autistic phenotypes, yet whether this mouse model is appropriate to study psychiatric comorbidity in ASD remains unclear. We addressed this issue by subjecting the BTBR animals to three-chambered apparatus, open field, object attention test and elevated open platform. Compared to C57BL/6J control mice, the BTBR mice displayed hyperactivity in most of the tests. In the three-chamber assessment, they exhibited deficits in sociability. In the open field, more grooming and thigmotaxis and less rearing behaviors were observed. They also showed impaired object-based attention. On the elevated open platform, the BTBR animals stayed more to the edges than in the center of the platform. To further examine the properties of this test, naïve C57BL/6J mice were randomly administrated with saline or an anxiogenic substance, caffeine. The caffeine group demonstrated a similar behavioral pattern as the BTBR mice. When the saline group was re-exposed to the same platform, the time they stayed in the center substantially increased, likely due to reduced anxiety by habituation. These results indicate that the BTBR were more anxious than control mice on the open platform. Taken together, the BTBR strain exhibit emotional and cognitive impairments in addition to autistic behaviors, suggesting that they can be a valid model for ASD with psychiatric comorbidity.

Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene.

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention. RESULTS: The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala. CONCLUSIONS: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model.

Interaction between the medial prefrontal cortex and hippocampal CA1 area is essential for episodic-like memory in rats.

The interplay between medial prefrontal cortex (mPFC) and hippocampus, particularly the hippocampal CA3 area, is critical for episodic memory. To what extent the mPFC also interacts with the hippocampus CA1 subregion still requires elucidation. To investigate this issue, male rats received unilateral N-methyl-D-aspartate lesions of the mPFC together with unilateral lesions of the hippocampal CA1 area, either in the same (control) or in the opposite hemispheres (disconnection). They underwent an episodic-like memory test, combining what-where-when information, and separate tests for novel object preference (what), object place preference (where) and temporal order memory (when). Compared to controls, the disconnected mPFC-CA1 rats exhibited disrupted episodic-like memory with an impaired integration of the what-where-when elements. Both groups showed intact memories for what and when, while only the control group showed intact memory for where. These findings suggest that the functional interaction of the mPFC-CA1 circuit is crucial for the processing of episodic memory and, in particular, for the integration of the spatial memory component.