How does cognition regulate innate behaviors? While the cognitive functions of the cortex have been extensively studied, we know much less about how cognition can regulate innate motivated behaviors ...to fulfill physiological, safety and social needs. Selection of appropriate motivated behaviors depends on external stimuli and past experiences that helps to scale priorities. With its abundant inputs from neocortical and allocortical regions, the lateral septum (LS) is ideally positioned to integrate perception and experience signals in order to regulate the activity of hypothalamic and midbrain nuclei that control motivated behaviors. In addition, LS receives numerous subcortical modulatory inputs, which represent the animal internal states and also participate in this regulation. In this perspective, we argue that LS sub-circuits regulate distinct motivated behaviors by integrating neural activity from neocortical, allocortical and neuromodulatory inputs. In addition, we propose that lateral inhibition between LS sub-circuits may allow the emergence of functional units that orchestrates competing motivated behaviors.
The consolidation of spatial memory depends on the reactivation ('replay') of hippocampal place cells that were active during recent behaviour. Such reactivation is observed during sharp-wave ripples ...(SWRs)-synchronous oscillatory electrical events that occur during non-rapid-eye-movement (non-REM) sleep
and whose disruption impairs spatial memory
. Although the hippocampus also encodes a wide range of non-spatial forms of declarative memory, it is not yet known whether SWRs are necessary for such memories. Moreover, although SWRs can arise from either the CA3 or the CA2 region of the hippocampus
, the relative importance of SWRs from these regions for memory consolidation is unknown. Here we examine the role of SWRs during the consolidation of social memory-the ability of an animal to recognize and remember a member of the same species-focusing on CA2 because of its essential role in social memory
. We find that ensembles of CA2 pyramidal neurons that are active during social exploration of previously unknown conspecifics are reactivated during SWRs. Notably, disruption or enhancement of CA2 SWRs suppresses or prolongs social memory, respectively. Thus, SWR-mediated reactivation of hippocampal firing related to recent experience appears to be a general mechanism for binding spatial, temporal and sensory information into high-order memory representations, including social memory.
Recent results suggest that social memory requires the dorsal hippocampal CA2 region as well as a subset of ventral CA1 neurons. However, it is unclear whether dorsal CA2 and ventral CA1 represent ...parallel or sequential circuits. Moreover, because evidence implicating CA2 in social memory comes largely from long-term inactivation experiments, the dynamic role of CA2 in social memory remains unclear. Here, we use pharmacogenetics and optogenetics in mice to acutely and reversibly silence dorsal CA2 and its projections to ventral hippocampus. We show that dorsal CA2 activity is critical for encoding, consolidation, and recall phases of social memory. Moreover, dorsal CA2 contributes to social memory by providing strong excitatory input to the same subregion of ventral CA1 that contains the subset of neurons implicated in social memory. Thus, our studies provide new insights into a dorsal CA2 to ventral CA1 circuit whose dynamic activity is necessary for social memory.
Although the hippocampus is known to be important for declarative memory, it is less clear how hippocampal output regulates motivated behaviours, such as social aggression. Here we report that ...pyramidal neurons in the CA2 region of the hippocampus, which are important for social memory, promote social aggression in mice. This action depends on output from CA2 to the lateral septum, which is selectively enhanced immediately before an attack. Activation of the lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventromedial hypothalamus that is known to trigger attack. The social hormone arginine vasopressin enhances social aggression by acting on arginine vasopressin 1b receptors on CA2 presynaptic terminals in the lateral septum to facilitate excitatory synaptic transmission. In this manner, release of arginine vasopressin in the lateral septum, driven by an animal's internal state, may serve as a modulatory control that determines whether CA2 activity leads to declarative memory of a social encounter and/or promotes motivated social aggression.
The hippocampus is essential for different forms of declarative memory, including social memory, the ability to recognize and remember a conspecific. Although recent studies identify the importance ...of the dorsal CA2 region of the hippocampus in social memory storage, little is known about its sources of social information. Because CA2, like other hippocampal regions, receives its major source of spatial and non-spatial information from the medial and lateral subdivisions of entorhinal cortex (MEC and LEC), respectively, we investigated the importance of these inputs for social memory. Whereas MEC inputs to CA2 are dispensable, the direct inputs to CA2 from LEC are both selectively activated during social exploration and required for social memory. This selective behavioral role of LEC is reflected in the stronger excitatory drive it provides to CA2 compared with MEC. Thus, a direct LEC → CA2 circuit is tuned to convey social information that is critical for social memory.
•Lateral entorhinal cortex (LEC) inputs to hippocampal CA2 underlie social memory•Medial entorhinal cortex (MEC) CA2 input is weak and not involved in social memory•Social memory requires the direct but not indirect LEC inputs to CA2•LEC CA2 inputs are selectively activated by social over non-social exploration
Although the CA2 hippocampal region is essential for social memory and detection of social novelty, the inputs that provide social information to CA2 are unknown. We found that social memory depends on the direct inputs CA2 receives from the lateral entorhinal cortex. As this input is activated similarly by novel and familiar individuals, CA2 itself may compute novelty.
Input-timing-dependent plasticity (ITDP) is a circuit-based synaptic learning rule by which paired activation of entorhinal cortical (EC) and Schaffer collateral (SC) inputs to hippocampal CA1 ...pyramidal neurons (PNs) produces a long-term enhancement of SC excitation. We now find that paired stimulation of EC and SC inputs also induces ITDP of SC excitation of CA2 PNs. However, whereas CA1 ITDP results from long-term depression of feedforward inhibition (iLTD) as a result of activation of CB1 endocannabinoid receptors on cholecystokinin-expressing interneurons, CA2 ITDP results from iLTD through activation of δ-opioid receptors on parvalbumin-expressing interneurons. Furthermore, whereas CA1 ITDP has been previously linked to enhanced specificity of contextual memory, we find that CA2 ITDP is associated with enhanced social memory. Thus, ITDP may provide a general synaptic learning rule for distinct forms of hippocampal-dependent memory mediated by distinct hippocampal regions.
•CA2 shows input-timing-dependent plasticity after pairing of its EC and SC inputs•CA2 ITDP results from long-term depression of PV+ IN feedforward inhibition•CA2 ITDP relies on activation of δ-opioid receptors expressed in PV+ INs•CA2 ITDP potentiates net SC→CA2 excitation and is associated with social memory
Paired activation of cortical and hippocampal inputs induces input-timing-dependent plasticity (ITDP) in CA1 neurons, enhancing contextual memory specificity. Here, Leroy et al. report that a distinct form of ITDP is associated with social memory storage in CA2 neurons.
Social preference, the decision to interact with one member of the same species over another, is critical to optimize social interactions. Thus, adult rodents favor interacting with novel ...conspecifics over familiar ones, but whether this social preference stems from neural circuits facilitating interactions with novel individuals or suppressing interactions with familiar ones remains unknown. Here, we identify neurons in the infra-limbic area (ILA) of the mouse prefrontal cortex that express the neuropeptide corticotropin-releasing hormone (CRH) and project to the dorsal region of the rostral lateral septum (rLS). We show how release of CRH during familiar encounters disinhibits rLS neurons, thereby suppressing social interactions with familiar mice and contributing to social novelty preference. We further demonstrate how the maturation of CRH expression in ILA during the first 2 post-natal weeks enables the developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults.
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•Release of CRH from PFC to LS suppresses social interaction with familiar mice•Suppression of social interaction with familiar mice supports social novelty preference•Maturation of this circuit induces a shift in social preference in young mice
Corticotropin-releasing hormone release from the infra-limbic area of the prefrontal cortex to the lateral septum suppresses social interaction with familiar but not novel mice to support the social novelty preference exhibited by adult mice. The maturation of this circuit during the first two post-natal weeks enables the developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults.
Amyotrophic lateral sclerosis （ALS） is a lethal disorder char- acterized by the gradual degeneration of brainstem and spinal motoneurons as well as lateral cortico-spinal tracts. The onset generally ...occurs during the adult age except for some juvenile aggressive forms. Until recently, the vast majority of the cases （90%） were deemed sporadic. Mutations in the SOD1 gene have been for a long time the only ones reported in familiar forms of ALS. However, the recent implication of new genes of little known function cast a new view on this disease. C9ORF72, for example, is now recognized to account for 30% of the familial cases. Overall, ALS has been linked to 20 different genes, many also associated with other degenerative diseases （frontotemporal dementia, Alzheimer or ataxia）. Some of these genes are in- volved in RNA maturation （FUS, TARBD）. Clinical observation of human patients and mouse models suggests that all motor pools and motoneurons are not equally affected （see Kanning et al., 2010）. The disease usually starts in motor pools controlling the limbs or in the bulbar area before expanding to other motor pools, with the exception of a few resistant ones （Onuf＇s and oculomotor nuclei）. Within a vulnerable motor pool, motoneu- tons subtypes also exhibit differential vulnerability and follow an orderly degeneration; starting with the motoneurons innervating fast-contracting fatigable motor units （IZF motoneurons） and followed by the ones innervating fast-contractile fatigue-resistant motor units （FR motoneurons）. The motoneurons in- nervating slow motor units （S motoneurons） appear resistant to the disease. Although the mechanisms leading to the orderly degeneration are not known, many hypotheses have been raised （Ilieva et al., 2009）.
The fast contraction time of mouse motor units creates a unique situation in which motoneurons have to fire at low frequencies to produce small forces but also at very high frequency (much higher ...than in cat or rat motoneurons) to reach the fusion frequency of their motor units. To understand how this problem is solved, we performed intracellular recordings of adult mouse spinal motoneurons and investigated systematically their subthreshold properties and their discharge pattern. We show that mouse motoneurons have a much wider range of firing frequencies than cat and rat motoneurons because of three salient features. First, they have a short membrane time constant. This results in a higher cutoff frequency and a higher resonance frequency, which allow mouse motoneurons to integrate inputs at higher frequencies. Second, their afterhyperpolarization (AHP) is faster, allowing the motoneurons to discharge at a higher rate. Third, motoneurons display high-frequency (100-150 Hz) subthreshold oscillations during the interspike intervals. The fast membrane kinetics greatly favors the appearance of these oscillations, creating a "subprimary range" of firing. In this range, which has never been reported in cat and in rat spinal motoneurons, the oscillations follow the AHP and trigger spiking after a variable delay, allowing a discharge at low frequency but at the expense of an irregular rate.
Molecular Mechanisms of the Memory Trace Asok, Arun; Leroy, Félix; Rayman, Joseph B. ...
Trends in neurosciences,
01/2019, Letnik:
42, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Over the past half-century, we have gained significant insights into the molecular biology of long-term memory storage at the level of the synapse. In recent years, our understanding of the cellular ...architecture supporting long-term memory traces has also substantially improved. However, the molecular biology of consolidation at the level of neuronal systems has been relatively neglected. In this opinion article, we first examine our current understanding of the cellular mechanisms of synaptic consolidation. We then outline areas requiring further investigation on how cellular changes contribute to systems consolidation. Finally, we highlight recent findings on the cellular architecture of memory traces in rodents and how the application of new technologies will expand our understanding of systems consolidation at the neural circuit level. In the coming years, this research focus will be critical for understanding the evolution of long-term memories and for enabling the development of novel therapeutics which embrace the dynamic nature of memories.
The molecular biology of synaptic consolidation is relatively well-defined. By contrast, the molecular mechanisms of systems consolidation remain poorly understood.
Recent technological developments have helped advance our understanding of the cellular representation of memories in the brain.
One of the goals of future research is to clarify how noncanonical forms of synaptic transmission (e.g., exosomally transported RNA, associated RNA-binding proteins, and epigenetic modifications to the transported RNA) may contribute to systems consolidation.
Integrating tools for examining these noncanonical cellular and molecular mechanisms with tools for tagging select circuits of a memory trace will be highly informative for elucidating the molecular mechanisms of systems consolidation.
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