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The anterior cingulate cortex allows an animal to update its behaviour when the environment changes. In this work, the authors identify a pathway from cingulate to secondary motor cortex, critical for updating motor rules following behavioural errors.

Where memories are located in our brains is not well understood. In this paper, the authors demonstrate that memories are spread out throughout multiple brain regions.

Learning from successes and failures often improves the quality of subsequent decisions. Past outcomes, however, should not influence purely perceptual decisions after task acquisition is complete since these are designed so that only sensory evidence determines the correct choice. Yet, numerous studies report that outcomes can bias perceptual decisions, causing spurious changes in choice behavior without improving accuracy. Here we show that the effects of reward on perceptual decisions are principled: past rewards bias future choices specifically when previous choice was difficult and hence decision confidence was low. We identified this phenomenon in six datasets from four laboratories, across mice, rats, and humans, and sensory modalities from olfaction and audition to vision. We show that this choice-updating strategy can be explained by reinforcement learning models incorporating statistical decision confidence into their teaching signals. Thus, reinforcement learning mechanisms are continually engaged to produce systematic adjustments of choices even in well-learned perceptual decisions in order to optimize behavior in an uncertain world.

Prior experience accelerates acquisition of novel, related information through processes like assimilation into mental schemas, but the underlying neuronal mechanisms are poorly understood. We investigated the roles that prior experience and hippocampal CA3 N-Methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity play in CA1 place cell sequence encoding and learning during novel spatial experiences. We found that specific representations of de novo experiences on linear environments were formed on a framework of pre configured network activity expressed in the preceding sleep and were rapidly, flexibly adjusted via NMDAR-dependent activity. This prior experience accelerated encoding of subsequent experiences on contiguous or isolated novel tracks, significantly decreasing their NMDAR-dependence. Similarly, de novo learning of an alternation task was facilitated by CA3 NMDARs; this experience accelerated subsequent learning of related tasks, independent of CA3 NMDARs, consistent with a schema-based learning. These results reveal the existence of distinct neuronal encoding schemes which could explain why hippocampal dysfunction results in anterograde amnesia while sparing recollection of old, schema-based memories.

Uterine leiomyosarcoma (LMS) develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Importantly, a diagnostic-biomarker which distinguishes malignant LMS from benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS, in order to establish a treatment method. LMP2-deficient mice spontaneously develop uterine LMS, with a disease prevalence of ~40% by 14 months of age. We found LMP2 expression to be absent in human LMS, but present in human LMA. Therefore, defective LMP2 expression may be one of the risk factors for LMS. LMP2 is a potential diagnostic-biomarker for uterine LMS, and may be targeted-molecule for a new therapeutic approach.

A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca(2+)-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice). Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP) that was independent of NMDARs and mediated by GluR2-lacking Ca(2+)-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca(2+)-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs.

Investigation confirm that the treatment of fetal thymic organ cultures with anti-CD3 epsilon monocloned antibodies in various T-cell receptor (TCR) beta-chain-deficient mouse strains can induce the CD4+8+ double-positive phase. The expression of CD3 epsilon on the thymocyte surface occurs before, regardless of the TCR beta chain.

In vitro mutagenesis analysis of the H-2T region gene product T22b gene, in which a self-reactive gamma delta T-cell clone (KN6) is specific, was used to explore the possible role of a peptide in the association between the KN6 gamma delta T-cell receptor and T22b. Recognition by the gamma delta T-cell receptor is influenced by mutations at the bottom of the putative antigen-binding groove of T22b. The association does involve a peptide.

Inflammatory bowel disease (IBD) simultaneously accompanies the phenomenon of aging in T cell receptor (TCR) mutant mice. The existence of B lymphocytes and the nonoccurrence of class II major histocompatibility complex-restricted CD4+ alpha-beta T cells are the prerequisites for the onset of chronic colitis in TCR alpha mutant, TCR beta mutant and TCR beta times delta double mutant. Molecular basis for the pathogenesis of certain kinds of IBD in humans may involve abnormal functioning of mucosal immune system.

Researches on mice with no alpha-beta or gamma-delta T cells and infected with listeria monocytogenes revealed that secondary infection resistance is primarily due to alpha-beta T cells. Abnormal lever lesions were observed in infected mice with deficiency in gamma-delta T cells. Either alpha-beta or gamma-delta T cells are adequate for initial protection against primary listeriosis. The formation of granulomatous lesions is determined by the alpha-beta T cell subset.

The anti T-cell receptor monoclonal antibody-mediated redirected lysis formed the base for attempts to explore the cytolytic action of newly isolated intraepithelial T cells (i-/EL) from the intestines of various mouse strains. Unlike the cytolytic activity of alpha-beta-i-IEL, the activity of delta-i-/EL was strain dependent. The cytoxicity is regulated by at least a pair of genes expressed in hemopoietic cells. One of them is associated with the major histocompatibility complex.

Foreign protein peptide recognizing by T cells enables impairment prevention. This was predominantly observed in proteins attached to the major histocompatibility complex (MHC) class 1 molecules, which are responsible for peptide-endoplasmic reticulum binding. Two MHC class II locus genes encoding proteins are essential for a substantial peptides presence. Three genes are considered transporters associated with antigen processing (TAP 1 and TAP 2), and belong to the membrane translocating ATP-binding family.

The residues involved in the interaction with TCRS were altered resulting in the conversion of a nonselecting peptide into a mixture of selecting peptides. Self-peptides were derived from C57 BL/6 and employed in the experiment which revealed that self-peptides influence the properties of CD8+ T cells. Mice lacking in the specific gene which encodes the peptide dealing with antigen processing have been found to have lower levels of MH4 class I molecular and fewer CD8+ T cells.

The attentional control of behavior is a higher-order cognitive function that operates through attention and response inhibition. The locus coeruleus (LC), the main source of norepinephrine in the brain, is considered to be involved in attentional control by modulating the neuronal activity of the prefrontal cortex (PFC). However, evidence for the causal role of LC activity in attentional control remains elusive. Here, by using behavioral and optogenetic techniques, we investigate the effect of LC neuron activation or inhibition in operant tests measuring attention and response inhibition (i.e., a measure of impulsive behavior). We show that LC neuron stimulation increases goal-directed attention and decreases impulsivity, while its suppression exacerbates distractibility and increases impulsive responding. Remarkably, we found that attention and response inhibition are under the control of two divergent projections emanating from the LC: one to the dorso-medial PFC and the other to the ventro-lateral orbitofrontal cortex, respectively. These findings are especially relevant for those pathological conditions characterized by attention deficits and elevated impulsivity. [ABSTRACT FROM AUTHOR]

The memory for a new episode is formed immediately upon experience and can last up to a lifetime. It has been shown that the hippocampal network plays a fundamental role in the rapid acquisition of a memory of a one-time experience, in which the novelty component of the experience promotes the prompt formation of the memory. However, it remains unclear which neural circuits convey the novelty signal to the hippocampus for the singletrial learning. Here, we show that during encoding neuromodulatory input from locus coeruleus (LC) to CA3, but not CA1 or to the dentate gyrus, is necessary to facilitate novel contextual learning. Silencing LC activity during exposure to a novel context reduced subsequent reactivation of the engram cell ensembles in CA3 neurons and in downstream CA1 upon reexposure to the same context. Calcium imaging of the cells reactivated in both novel and familiar contexts revealed that suppression of LC inputs at the time of encoding resulted in more variable place fields in CA3 neurons. These results suggest that neuromodulatory input from LC to CA3 is crucial for the formation of a persistent memory in the hippocampus. [ABSTRACT FROM AUTHOR]

The mechanism of memory remains one of the great unsolved problems of biology. Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of the engram, lasting connections in the brain that result from simultaneous "excitations", whose precise physical nature and consequences were out of reach of the biology of his day. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today. [ABSTRACT FROM AUTHOR]

Entorhinal-hippocampal circuits in the mammalian brain are crucial for an animal's spatial and episodic experience, but the neural basis for different spatial computations remain unknown. Medial entorhinal cortex layer II contains pyramidal island and stellate ocean cells. Here, we performed cell type-specific Ca2+ imaging in freely exploring mice using cellular markers and a miniature head-mounted fluorescence microscope. We found that both oceans and islands contain grid cells in similar proportions, but island cell activity, including activity in a proportion of grid cells, is significantly more speed modulated than ocean cell activity. We speculate that this differential property reflects island cells' and ocean cells' contribution to different downstream functions: island cells may contribute more to spatial path integration, whereas ocean cells may facilitate contextual representation in downstream circuits. [ABSTRACT FROM AUTHOR]

Internal representations about the external world can be driven by the external stimuli or can be internally generated in their absence. It has been a matter of debate whether novel stimuli from the external world are instructive over the brain network to create de novo representations or, alternatively, are selecting from existing pre-representations hosted in preconfigured brain networks. The hippocampus is a brain area necessary for normal internally generated spatial-temporal representations and its dysfunctions have resulted in anterograde amnesia, impaired imagining of new experiences, and hallucinations. The compressed temporal sequence of place cell activity in the rodent hippocampus serves as an animal model of internal representation of the external space. Based on our recent results on the phenomenon of novel place cell sequence preplay, we submit that the place cell sequence of a novel spatial experience is determined, in part, by a selection of a set of cellular firing sequences from a repertoire of existing temporal firing sequences in the hippocampal network. Conceptually, this indicates that novel stimuli from the external world select from their pre-representations rather than create de novo our internal representations of the world. [ABSTRACT FROM AUTHOR]

Memories can be easily distorted, and a lack of relevant animal models has largely hindered our understanding of false-memory formation. Here, we first identified a population of cells in the dentate gyrus (DG) of the hippocampus that bear the engrams for a specific context; these cells were naturally activated during the encoding phase of fear conditioning and their artificial reactivation using optogenetics in an unrelated context was sufficient for inducing the fear memory specific to the conditioned context. In a further study, DG or CA1 neurons activated by exposure to a particular context were labelled with channelrhodopsin-2 (ChR2). These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context in which a foot shock was never delivered. The recall of this false memory was context specific, activated similar downstream regions engaged during natural fear-memory recall, and was also capable of driving an active fear response. Together, our data demonstrate that by substituting a natural conditioned stimulus with optogenetically reactivated DG cells that bear contextual memory engrams, it is possible to incept an internally and behaviourally represented false fear memory. [ABSTRACT FROM AUTHOR]

Since lumenal bacteria have been postulated to play an Important role in the pathogenesls of inflammatory bowel disease (IBD), we investigated the humoral response to cecal aerobic bacterial antigens by Western blot analysis in TCRα-/- mice which spontaneously develop IBD. The sera from TCRα-/- mice revealed an alteration of the recognition pattern against aerobic bacterial antigens from polyclonal to oligoclonal with age. This alteration was not observed in TCRδ-/- and TCRα+/- mice. The alteration of the recognition pattern in TCRα-/- mice was associated with production of autoantibodies against tropomyosin and the development of IBD. The unique population of CD4+ TCR-β+ cells In TCRα-/- mice may be involved In the recognition of these bacterial antigens and the absence of the α chain may result in the alteration of immune response. [ABSTRACT FROM AUTHOR]

The medial temporal lobe, including the hippocampus, has been implicated in social memory. However, it remains unknown which parts of these brain regions and their circuits hold social memory. Here, we show that ventral hippocampal CA1 (vCA1) neurons of a mouse and their projections to nucleus accumbens (NAc) shell play a necessary and sufficient role in social memory. Both the proportion of activated vCA1 cells and the strength and stability of the responding cells are greater in response to a familiar mouse than to a previously unencountered mouse. Optogenetic reactivation of vCA1 neurons that respond to the familiar mouse enabled memory retrieval and the association of these neurons with unconditioned stimuli. Thus, vCA1 neurons and their NAc shell projections are a component of the storage site of social memory. [ABSTRACT FROM AUTHOR]

Episodic memory requires associations of temporally discontiguous events. In the entorhinal-hippocampal network, temporal associations are driven by a direct pathway from layer III of the medial entorhinal cortex (MECIII) to the hippocampal CA1 region. However, the identification of neural circuits that regulate this association has remained unknown. In Layer II of entorhinal cortex (ECII), we report clusters of excitatory neurons called island cells, which appear in a curvilinear matrix of bulblike structures, directly project to CA1, and activate interneurons that target the distal dendrites of CA1 pyramidal neurons. Island cells suppress the excitatory MECIII input through the feed-forward inhibition to control the strength and duration of temporal association in trace fear memory. Together, the two EC inputs compose a control circuit for temporal association memory. [ABSTRACT FROM AUTHOR]

The article presents a study on how memories are formed and stored in the brain. Topics include the evolution of the engram theory of memory that was first conceived by German biologist Richard Semons, the system developed by the researchers of the study in identifying and manipulating memory engram cells in the brain known as optogenetics, , and how these methods can address questions such as how false memory is formed and how the valence of a memory can be changed in the brain.

cific for myelin basic protein (MBP) and crossed them to RAG-1-deficient mice to obtain mice (T/R-) that have T cells expressing the transgenic TCR but no other lymphocytes. Both T/R+ and T/R- mice carry, in the lymph nodes and spleen, large numbers of the potentially encephalitogenic CD4+ anti-MBP T cells. These cells respond to MBP in vitro but show no signs of activation in vivo. Nevertheless, - 1 4% of H-2U T/R+ and 100% of H-2U T/R mice developed spontaneous experimental autoimmune encephalomyelitis (EAE) within 12 months. These data indicate that EAE can be mediated by CD4+ anti-MBP T cells in the absence of any other lymphocytes and that nontransgenic lymphocytes that are present in T/R+ but absent in T/R- mice have a protective effect. The data also suggest that spontaneous EAE may be triggered by an in situ activation of CD4+ anti-MBP cells in the nervous system. [ABSTRACT FROM AUTHOR]