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1.
bioRxiv ; 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38464058

ABSTRACT

Hippocampal pyramidal neurons support episodic memory by integrating complementary information streams into new 'place fields'. Distal tuft dendrites are widely thought to initiate place field formation by locally generating prolonged, globally-spreading Ca 2+ spikes known as plateau potentials. However, the hitherto experimental inaccessibility of distal tuft dendrites in the hippocampus has rendered their in vivo function entirely unknown. Here we gained direct optical access to this elusive dendritic compartment. We report that distal tuft dendrites do not serve as the point of origin for place field-forming plateau potentials. Instead, the timing and extent of peri-formation distal tuft recruitment is variable and closely predicts multiple properties of resultant place fields. Therefore, distal tuft dendrites play a more powerful role in hippocampal feature selectivity than simply initiating place field formation. Moreover, place field formation is not accompanied by global Ca 2+ influx as previously thought. In addition to shaping new somatic place fields, distal tuft dendrites possess their own local place fields. Tuft place fields are back-shifted relative to that of their soma and appear to maintain somatic place fields via post-formation plateau potentials. Through direct in vivo observation, we provide a revised dendritic basis for hippocampal feature selectivity during navigational learning.

2.
Science ; 375(6586): eabm1670, 2022 03 18.
Article in English | MEDLINE | ID: mdl-35298275

ABSTRACT

Dendritic calcium signaling is central to neural plasticity mechanisms that allow animals to adapt to the environment. Intracellular calcium release (ICR) from the endoplasmic reticulum has long been thought to shape these mechanisms. However, ICR has not been investigated in mammalian neurons in vivo. We combined electroporation of single CA1 pyramidal neurons, simultaneous imaging of dendritic and somatic activity during spatial navigation, optogenetic place field induction, and acute genetic augmentation of ICR cytosolic impact to reveal that ICR supports the establishment of dendritic feature selectivity and shapes integrative properties determining output-level receptive fields. This role for ICR was more prominent in apical than in basal dendrites. Thus, ICR cooperates with circuit-level architecture in vivo to promote the emergence of behaviorally relevant plasticity in a compartment-specific manner.


Subject(s)
CA1 Region, Hippocampal/physiology , Calcium/metabolism , Dendrites/physiology , Endoplasmic Reticulum/metabolism , Neuronal Plasticity , Place Cells/physiology , Action Potentials , Adaptor Proteins, Signal Transducing/genetics , Animals , Calcium Signaling , Cytosol/metabolism , Electroporation , Female , Male , Mice , Optogenetics , Single-Cell Analysis , Spatial Navigation
3.
Nature ; 601(7892): 240-244, 2022 01.
Article in English | MEDLINE | ID: mdl-34880499

ABSTRACT

Associative memories guide behavioural adaptation by binding together outcome-predictive sensory stimuli1,2. However, in a feature-rich environment, only a subset of stimuli may predict a desired outcome3,4. How neural circuits enable behavioural adaptation by selectively and durably representing subsets of sensory stimuli that are pertinent to a specific outcome is not known. We investigated this feature selection process in the hippocampus during memory acquisition and subsequent consolidation. Two-photon calcium imaging of CA3 axonal projections to CA1 combined with simultaneous local field potential recordings revealed that CA3 projections that encode behaviourally informative sensory stimuli were selectively recruited during the memory replay events that underlie hippocampal memory consolidation5. These axonal projections formed sequential assemblies that conjunctively link sensory features to spatial location and thus reward proximity. By contrast, axons encoding uninformative, peripatetic sensory cues were notably suppressed during memory replay. Thus, while the hippocampus comprehensively encodes the real-time sensory environment, it implements a flexible filtering mechanism to maximize the utility of memories destined for long-term storage. We propose that utility-dependent recruitment of sensory experience during memory consolidation is a general coding principle for associative learning.


Subject(s)
Hippocampus , Memory Consolidation , Conditioning, Classical , Memory , Reward
4.
Neuron ; 101(6): 1150-1165.e8, 2019 03 20.
Article in English | MEDLINE | ID: mdl-30713030

ABSTRACT

Diverse computations in the neocortex are aided by specialized GABAergic interneurons (INs), which selectively target other INs. However, much less is known about how these canonical disinhibitory circuit motifs contribute to network operations supporting spatial navigation and learning in the hippocampus. Using chronic two-photon calcium imaging in mice performing random foraging or goal-oriented learning tasks, we found that vasoactive intestinal polypeptide-expressing (VIP+), disinhibitory INs in hippocampal area CA1 form functional subpopulations defined by their modulation by behavioral states and task demands. Optogenetic manipulations of VIP+ INs and computational modeling further showed that VIP+ disinhibition is necessary for goal-directed learning and related reorganization of hippocampal pyramidal cell population dynamics. Our results demonstrate that disinhibitory circuits in the hippocampus play an active role in supporting spatial learning. VIDEO ABSTRACT.


Subject(s)
CA1 Region, Hippocampal/cytology , Interneurons/physiology , Neural Inhibition/physiology , Pyramidal Cells/physiology , Spatial Learning/physiology , Animals , Appetitive Behavior/physiology , CA1 Region, Hippocampal/physiology , Goals , Hippocampus/cytology , Hippocampus/physiology , Interneurons/cytology , Interneurons/metabolism , Mice , Neocortex/cytology , Neocortex/physiology , Optogenetics , Pyramidal Cells/cytology , Vasoactive Intestinal Peptide/metabolism
5.
Curr Opin Behav Sci ; 20: 40-46, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29450220

ABSTRACT

Habits have been studied for decades, but it was not until recent years that experiments began to elucidate the underlying cellular and circuit mechanisms. The latest experiments have been enabled by advances in cell-type specific monitoring and manipulation of activity in large neuronal populations. Here we will review recent efforts to understand the neural substrates underlying habit formation, focusing on rodent studies on corticostriatal circuits.

6.
Neuropsychopharmacology ; 43(5): 953-963, 2018 04.
Article in English | MEDLINE | ID: mdl-28840858

ABSTRACT

To determine the requirement for parvalbumin (PV) expressing GABAergic interneurons of the nucleus accumbens (NAc) in the behavioral adaptations induced by amphetamine (AMPH), we blocked synaptic vesicle release from these neurons using Cre-inducible viral expression of the tetanus toxin light chain in male and female PV-Cre mice. Silencing PV+ interneurons of the NAc selectively inhibited the expression of locomotor sensitization following repeated injections of AMPH and blocked AMPH-induced conditioned place preference (CPP). AMPH induced significantly more expression of the activity-dependent gene Fos in both D1 and D2 dopamine receptor-expressing medium spiny neurons (MSNs) of the NAc of PV+ interneuron silenced mice, suggesting a function for PV+ interneuron-mediated MSN inhibition in the expression of AMPH-induced locomotor sensitization and CPP. These data show a requirement for PV+ interneurons of the NAc in behavioral responses to AMPH, and they raise the possibility that modulation of PV+ interneuron function may alter the development or expression of psychostimulant-induced behavioral adaptations.


Subject(s)
Amphetamine/pharmacology , Central Nervous System Sensitization/drug effects , Conditioning, Psychological/drug effects , Interneurons/drug effects , Locomotion/drug effects , Nucleus Accumbens/cytology , Parvalbumins/metabolism , Animals , Female , Genetic Vectors , Interneurons/metabolism , Male , Metalloendopeptidases/genetics , Mice , Nucleus Accumbens/drug effects , Tetanus Toxin/genetics
7.
Elife ; 62017 09 05.
Article in English | MEDLINE | ID: mdl-28871960

ABSTRACT

Habit formation is a behavioral adaptation that automates routine actions. Habitual behavior correlates with broad reconfigurations of dorsolateral striatal (DLS) circuit properties that increase gain and shift pathway timing. The mechanism(s) for these circuit adaptations are unknown and could be responsible for habitual behavior. Here we find that a single class of interneuron, fast-spiking interneurons (FSIs), modulates all of these habit-predictive properties. Consistent with a role in habits, FSIs are more excitable in habitual mice compared to goal-directed and acute chemogenetic inhibition of FSIs in DLS prevents the expression of habitual lever pressing. In vivo recordings further reveal a previously unappreciated selective modulation of SPNs based on their firing patterns; FSIs inhibit most SPNs but paradoxically promote the activity of a subset displaying high fractions of gamma-frequency spiking. These results establish a microcircuit mechanism for habits and provide a new example of how interneurons mediate experience-dependent behavior.


Subject(s)
Action Potentials/physiology , Behavior, Animal , Habituation, Psychophysiologic , Interneurons/physiology , Neostriatum/physiology , Nerve Net/physiology , Animals , Calcium/metabolism , Endophenotypes , Mice, Inbred C57BL , Models, Neurological , Neuronal Plasticity/physiology , Optogenetics , Parvalbumins/metabolism
8.
Biol Psychiatry ; 80(7): 522-33, 2016 10 01.
Article in English | MEDLINE | ID: mdl-27436084

ABSTRACT

BACKGROUND: Development of treatments for obsessive-compulsive disorder (OCD) is hampered by a lack of mechanistic understanding about this prevalent neuropsychiatric condition. Although circuit changes such as elevated frontostriatal activity are linked to OCD, the underlying molecular signaling that drives OCD-related behaviors remains largely unknown. Here, we examine the significance of type 5 metabotropic glutamate receptors (mGluR5s) for behavioral and circuit abnormalities relevant to OCD. METHODS: Sapap3 knockout (KO) mice treated acutely with an mGluR5 antagonist were evaluated for OCD-relevant phenotypes of self-grooming, anxiety-like behaviors, and increased striatal activity. The role of mGluR5 in the striatal circuit abnormalities of Sapap3 KO mice was further explored using two-photon calcium imaging to monitor striatal output from the direct and indirect pathways. A contribution of constitutive signaling to increased striatal mGluR5 activity in Sapap3 KO mice was investigated using pharmacologic and biochemical approaches. Finally, sufficiency of mGluR5 to drive OCD-like behavior in wild-type mice was tested by potentiating mGluR5 with a positive allosteric modulator. RESULTS: Excessive mGluR5 signaling underlies OCD-like behaviors and striatal circuit abnormalities in Sapap3 KO mice. Accordingly, enhancing mGluR5 activity acutely recapitulates these behavioral phenotypes in wild-type mice. In Sapap3 KO mice, elevated mGluR5 signaling is associated with constitutively active receptors and increased and imbalanced striatal output that is acutely corrected by antagonizing striatal mGluR5. CONCLUSIONS: These findings demonstrate a causal role for increased mGluR5 signaling in driving striatal output abnormalities and behaviors with relevance to OCD and show the tractability of acute mGluR5 inhibition to remedy circuit and behavioral abnormalities.


Subject(s)
Corpus Striatum/physiopathology , Obsessive-Compulsive Disorder/physiopathology , Receptor, Metabotropic Glutamate 5/physiology , Signal Transduction , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Grooming/drug effects , Grooming/physiology , Mice , Mice, Knockout , Mice, Transgenic , Nerve Tissue Proteins/genetics , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Pyridines/pharmacology , Receptor, Metabotropic Glutamate 5/drug effects , Thiazoles/pharmacology
9.
Neuron ; 89(3): 472-9, 2016 Feb 03.
Article in English | MEDLINE | ID: mdl-26804995

ABSTRACT

The dorsolateral striatum (DLS) is implicated in habit formation. However, the DLS circuit mechanisms underlying habit remain unclear. A key role for DLS is to transform sensorimotor cortical input into firing of output neurons that project to the mutually antagonistic direct and indirect basal ganglia pathways. Here we examine whether habit alters this input-output function. By imaging cortically evoked firing in large populations of pathway-defined striatal projection neurons (SPNs), we identify features that strongly correlate with habitual behavior on a subject-by-subject basis. Habitual behavior correlated with strengthened DLS output to both pathways as well as a tendency for action-promoting direct pathway SPNs to fire before indirect pathway SPNs. In contrast, habit suppression correlated solely with a weakened direct pathway output. Surprisingly, all effects were broadly distributed in space. Together, these findings indicate that the striatum imposes broad, pathway-specific modulations of incoming activity to render learned motor behaviors habitual.


Subject(s)
Basal Ganglia/physiology , Corpus Striatum/physiology , Habits , Neural Pathways/physiology , Sensorimotor Cortex/physiology , Animals , Basal Ganglia/cytology , Brain Mapping , Conditioning, Operant/physiology , Corpus Striatum/cytology , Mice , Neurons/physiology , Optical Imaging , Reinforcement Schedule , Sensorimotor Cortex/cytology
10.
Nat Neurosci ; 15(8): 1114-6, 2012 Jun 26.
Article in English | MEDLINE | ID: mdl-22751035

ABSTRACT

Information acquired during waking can be reactivated during sleep, promoting memory stabilization. After people learned to produce two melodies in time with moving visual symbols, we enhanced relative performance by presenting one melody during an afternoon nap. Electrophysiological signs of memory processing during sleep corroborated the notion that appropriate auditory stimulation that does not disrupt sleep can nevertheless bias memory consolidation in relevant brain circuitry.


Subject(s)
Cues , Electroencephalography/methods , Memory/physiology , Sleep/physiology , Adult , Auditory Perception/physiology , Female , Humans , Learning/physiology , Male , Mental Recall/physiology , Music/psychology , Neuropsychological Tests , Recognition, Psychology/physiology , Young Adult
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