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A cellular basis for mapping behavioural structure.
To flexibly adapt to new situations, our brains must understand the regularities in the world, as well as those in our own patterns of behaviour. A wealth of findings is beginning to reveal the algorithms that we use to map the outside world1-6. However, the biological algorithms that map the complex structured behaviours that we compose to reach our goals remain unknown. Here we reveal a neuronal implementation of an algorithm for mapping abstract behavioural structure and transferring it to new scenarios. We trained mice on many tasks that shared a common structure (organizing a sequence of goals) but differed in the specific goal locations. The mice discovered the underlying task structure, enabling zero-shot inferences on the first trial of new tasks. The activity of most neurons in the medial frontal cortex tiled progress to goal, akin to how place cells map physical space. These 'goal-progress cells' generalized, stretching and compressing their tiling to accommodate different goal distances. By contrast, progress along the overall sequence of goals was not encoded explicitly. Instead, a subset of goal-progress cells was further tuned such that individual neurons fired with a fixed task lag from a particular behavioural step. Together, these cells acted as task-structured memory buffers, implementing an algorithm that instantaneously encoded the entire sequence of future behavioural steps, and whose dynamics automatically computed the appropriate action at each step. These dynamics mirrored the abstract task structure both on-task and during offline sleep. Our findings suggest that schemata of complex behavioural structures can be generated by sculpting progress-to-goal tuning into task-structured buffers of individual behavioural steps.
Left-right dissociation of hippocampal memory processes in mice.
Left-right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3-CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left-right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left-right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory.
The shallow cognitive map hypothesis: A hippocampal framework for thought disorder in schizophrenia.
Memories are not formed in isolation. They are associated and organized into relational knowledge structures that allow coherent thought. Failure to express such coherent thought is a key hallmark of Schizophrenia. Here we explore the hypothesis that thought disorder arises from disorganized Hippocampal cognitive maps. In doing so, we combine insights from two key lines of investigation, one concerning the neural signatures of cognitive mapping, and another that seeks to understand lower-level cellular mechanisms of cognition within a dynamical systems framework. Specifically, we propose that multiple distinct pathological pathways converge on the shallowing of Hippocampal attractors, giving rise to disorganized Hippocampal cognitive maps and driving conceptual disorganization. We discuss the available evidence at the computational, behavioural, network, and cellular levels. We also outline testable predictions from this framework, including how it could unify major chemical and psychological theories of schizophrenia and how it can provide a rationale for understanding the aetiology and treatment of the disease.
An emergent neural coactivity code for dynamic memory.
Neural correlates of external variables provide potential internal codes that guide an animal's behavior. Notably, first-order features of neural activity, such as single-neuron firing rates, have been implicated in encoding information. However, the extent to which higher-order features, such as multineuron coactivity, play primary roles in encoding information or secondary roles in supporting single-neuron codes remains unclear. Here, we show that millisecond-timescale coactivity among hippocampal CA1 neurons discriminates distinct, short-lived behavioral contingencies. This contingency discrimination was unrelated to the tuning of individual neurons, but was instead an emergent property of their coactivity. Contingency-discriminating patterns were reactivated offline after learning, and their reinstatement predicted trial-by-trial memory performance. Moreover, optogenetic suppression of inputs from the upstream CA3 region during learning impaired coactivity-based contingency information in the CA1 and subsequent dynamic memory retrieval. These findings identify millisecond-timescale coactivity as a primary feature of neural firing that encodes behaviorally relevant variables and supports memory retrieval.
Integrating new memories into the hippocampal network activity space.
By investigating the topology of neuronal co-activity, we found that mnemonic information spans multiple operational axes in the mouse hippocampus network. High-activity principal cells form the core of each memory along a first axis, segregating spatial contexts and novelty. Low-activity cells join co-activity motifs across behavioral events and enable their crosstalk along two other axes. This reveals an organizational principle for continuous integration and interaction of hippocampal memories.
A Hippocampus-Accumbens Tripartite Neuronal Motif Guides Appetitive Memory in Space.
Retrieving and acting on memories of food-predicting environments are fundamental processes for animal survival. Hippocampal pyramidal cells (PYRs) of the mammalian brain provide mnemonic representations of space. Yet the substrates by which these hippocampal representations support memory-guided behavior remain unknown. Here, we uncover a direct connection from dorsal CA1 (dCA1) hippocampus to nucleus accumbens (NAc) that enables the behavioral manifestation of place-reward memories. By monitoring neuronal ensembles in mouse dCA1→NAc pathway, combined with cell-type selective optogenetic manipulations of input-defined postsynaptic neurons, we show that dCA1 PYRs drive NAc medium spiny neurons and orchestrate their spiking activity using feedforward inhibition mediated by dCA1-connected parvalbumin-expressing fast-spiking interneurons. This tripartite cross-circuit motif supports spatial appetitive memory and associated NAc assemblies, being independent of dorsal subiculum and dispensable for both spatial novelty detection and reward seeking. Our findings demonstrate that the dCA1→NAc pathway instantiates a limbic-motor interface for neuronal representations of space to promote effective appetitive behavior.
Optogenetic Methods to Study Lateralized Synaptic Function
This volume explores both simple and sophisticated techniques used in the study of different types of lateralization of brain and behavior.
Archaerhodopsin Selectively and Reversibly Silences Synaptic Transmission through Altered pH.
Tools that allow acute and selective silencing of synaptic transmission in vivo would be invaluable for understanding the synaptic basis of specific behaviors. Here, we show that presynaptic expression of the proton pump archaerhodopsin enables robust, selective, and reversible optogenetic synaptic silencing with rapid onset and offset. Two-photon fluorescence imaging revealed that this effect is accompanied by a transient increase in pH restricted to archaerhodopsin-expressing boutons. Crucially, clamping intracellular pH abolished synaptic silencing without affecting the archaerhodopsin-mediated hyperpolarizing current, indicating that changes in pH mediate the synaptic silencing effect. To verify the utility of this technique, we used trial-limited, archaerhodopsin-mediated silencing to uncover a requirement for CA3-CA1 synapses whose afferents originate from the left CA3, but not those from the right CA3, for performance on a long-term memory task. These results highlight optogenetic, pH-mediated silencing of synaptic transmission as a spatiotemporally selective approach to dissecting synaptic function in behaving animals.
Synaptic Plasticity and Memory: New Insights from Hippocampal Left-Right Asymmetries.
All synapses are not the same. They differ in their morphology, molecular constituents, and malleability. A striking left-right asymmetry in the distribution of different types of synapse was recently uncovered at the CA3-CA1 projection in the mouse hippocampus, whereby afferents from the CA3 in the left hemisphere innervate small, highly plastic synapses on the apical dendrites of CA1 pyramidal neurons, whereas those originating from the right CA3 target larger, more stable synapses. Activity-dependent modification of these synapses is thought to participate in circuit formation and remodeling during development, and further plastic changes may support memory encoding in adulthood. Therefore, exploiting the CA3-CA1 asymmetry provides a promising opportunity to investigate the roles that different types of synapse play in these fundamental properties of the CNS. Here we describe the discovery of these segregated synaptic populations in the mouse hippocampus, and discuss what we have already learnt about synaptic plasticity from this asymmetric arrangement. We then propose models for how the asymmetry could be generated during development, and how the adult hippocampus might use these distinct populations of synapses differentially during learning and memory. Finally, we outline the potential implications of this left-right asymmetry for human hippocampal function, as well as dysfunction in memory disorders such as Alzheimer's disease.
Harmonising flavours: How arousing music and sound influence food perception and emotional responses
This study aims to provide a novel understanding of how music and sound varying in arousal can affect temporal changes in food perception and the corresponding emotional responses, measured through both subjective and objective (i.e., electrophysiological) methods. Exciting conditions are associated with low valence and high arousal, whereas calm conditions are associated with high valence and low arousal. Calm music (CM), calm sound (CS), and a combination of calm music and sound (CMCS) evoked emotions such as joy, relaxation, calmness, pleasantness, and at ease, and were correlated with the perception of sweetness and creaminess. Conversely, exciting music (EM) increased arousal, evoked emotions such as, activity, enthusiasm, energy, and excitement, and amplified the perception of roasted and bitter flavours. Exciting sounds (ES) and combined exciting music and exciting sound (EMES) conditions were positively correlated with anxiety, fatigue, unease, unhappiness, difficulty concentrating, irritation, and restlessness, as well as enhancing the perception of roasted and bitter flavours. Furthermore, the EM and EMES conditions gave rise to significantly higher skin conductance and respiration rate, with corresponding correlations with the perception of roasted and bitter flavours. The ES and EMES conditions demonstrated significantly higher heart rate and respiration rate. The CM condition showed significantly higher heart rate and emotional responses while the CS condition showed significantly higher skin conductance. The findings of this study indicate that sensory attributes are closely associated with the emotions and physiological responses evoked when consuming ice cream under different music and sound conditions.
Audiovisual Associations in Saint-Saëns’ Carnival of the Animals: A Cross-Cultural Investigation on the Role of Timbre
Several studies have investigated crossmodal associations involving audiovisual stimuli. To date, however, far fewer studies have explored the relationship between musical timbre and visual features (e.g., soft/harsh timbres with blue/red colours). To fill this gap in the literature, 249 participants were invited to judge the match between different coloured images and musical excerpts. The images depicted seven characters from Saint-Saëns’ “Carnival of the Animals”; the audio stimuli consisted of the music the composer created to represent each character. To test the effect of timbre and culture, the audio stimuli were presented either in the original orchestral version or in the piano transcription, while the participants were recruited from various countries, encompassing both Western and non-Western nationalities. The results demonstrate that timbre influences crossmodal associations between musical excerpts and drawings, while these associations remain consistent across cultures, languages, and levels of musical background.
The Nuffield Early Language Intervention (NELI) programme is associated with lasting improvements in children's language and reading skills.
BACKGROUND: Oral language skills are a critical foundation for education and psychosocial development. Learning to read, in particular, depends heavily on oral language skills. The Nuffield Early Language Intervention (NELI) has been shown to improve the language of 4-5-year-old children entering school with language weaknesses in four robust trials. To date, however, there is limited evidence on the durability of the gains produced by the intervention, and some have argued that the effects of such educational interventions typically fade-out quite rapidly. METHODS: A large-scale effectiveness trial of the NELI intervention implemented under real-world conditions produced educationally meaningful improvements in children's language and reading abilities. Here, we report follow-up testing of children from this study conducted approximately 2 years after the completion of the intervention. RESULTS: At 2-year follow-up, children who had received NELI had better oral language (d = 0.22 or d = 0.33 for children with lower language ability), reading comprehension (d = 0.16 or d = 0.24 for children with lower language ability) and single-word reading skills (d = 0.16 or d = 0.22 for children with lower language ability) than the control group. CONCLUSIONS: Our data show that, although fade-out effects are common in educational research, a widely used language intervention produces durable improvements in language and reading skills, with educationally important effect sizes. These findings have important theoretical and practical implications.