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1.
Proc Natl Acad Sci U S A ; 120(2): e2123182120, 2023 01 10.
Article in English | MEDLINE | ID: mdl-36598942

ABSTRACT

Early-life experience enduringly sculpts thalamocortical (TC) axons and sensory processing. Here, we identify the very first synaptic targets that initiate critical period plasticity, heralded by altered cortical oscillations. Monocular deprivation (MD) acutely induced a transient (<3 h) peak in EEG γ-power (~40 Hz) specifically within the visual cortex, but only when the critical period was open (juvenile mice or adults after dark-rearing, Lynx1-deletion, or diazepam-rescued GAD65-deficiency). Rapid TC input loss onto parvalbumin-expressing (PV) inhibitory interneurons (but not onto nearby pyramidal cells) was observed within hours of MD in a TC slice preserving the visual pathway - again once critical periods opened. Computational TC modeling of the emergent γ-rhythm in response to MD delineated a cortical interneuronal gamma (ING) rhythm in networks of PV-cells bearing gap junctions at the start of the critical period. The ING rhythm effectively dissociated thalamic input from cortical spiking, leading to rapid loss of previously strong TC-to-PV connections through standard spike-timing-dependent plasticity rules. As a consequence, previously silent TC-to-PV connections could strengthen on a slower timescale, capturing the gradually increasing γ-frequency and eventual fade-out over time. Thus, ING enables cortical dynamics to transition from being dominated by the strongest TC input to one that senses the statistics of population TC input after MD. Taken together, our findings reveal the initial synaptic events underlying critical period plasticity and suggest that the fleeting ING accompanying a brief sensory perturbation may serve as a robust readout of TC network state with which to probe developmental trajectories.


Subject(s)
Gamma Rhythm , Interneurons , Mice , Animals , Gamma Rhythm/physiology , Interneurons/physiology , Pyramidal Cells/physiology , Gap Junctions , Parvalbumins , Neuronal Plasticity/physiology
2.
Nature ; 538(7624): 253-256, 2016 Oct 13.
Article in English | MEDLINE | ID: mdl-27698417

ABSTRACT

Atypical food intake is a primary cause of obesity and other eating and metabolic disorders. Insight into the neural control of feeding has previously focused mainly on signalling mechanisms associated with the hypothalamus, the major centre in the brain that regulates body weight homeostasis. However, roles of non-canonical central nervous system signalling mechanisms in regulating feeding behaviour have been largely uncharacterized. Acetylcholine has long been proposed to influence feeding owing in part to the functional similarity between acetylcholine and nicotine, a known appetite suppressant. Nicotine is an exogenous agonist for acetylcholine receptors, suggesting that endogenous cholinergic signalling may play a part in normal physiological regulation of feeding. However, it remains unclear how cholinergic neurons in the brain regulate food intake. Here we report that cholinergic neurons of the mouse basal forebrain potently influence food intake and body weight. Impairment of cholinergic signalling increases food intake and results in severe obesity, whereas enhanced cholinergic signalling decreases food consumption. We found that cholinergic circuits modulate appetite suppression on downstream targets in the hypothalamus. Together our data reveal the cholinergic basal forebrain as a major modulatory centre underlying feeding behaviour.


Subject(s)
Appetite Regulation/physiology , Basal Forebrain/cytology , Basal Forebrain/physiology , Cholinergic Neurons/metabolism , Feeding Behavior/physiology , Satiety Response/physiology , Acetylcholine/metabolism , Animals , Body Weight/physiology , Cell Death , Choline O-Acetyltransferase/deficiency , Cholinergic Agonists , Cholinergic Neurons/pathology , Eating/physiology , Eating/psychology , Feeding Behavior/psychology , Female , Homeostasis , Hyperphagia/enzymology , Hyperphagia/genetics , Hyperphagia/pathology , Hypothalamus/cytology , Hypothalamus/physiology , Male , Mice , Mice, Knockout , Models, Neurological , Nicotine/metabolism , Obesity/enzymology , Obesity/genetics , Obesity/pathology , Receptors, Cholinergic/metabolism
3.
J Neurosci ; 36(34): 8856-71, 2016 08 24.
Article in English | MEDLINE | ID: mdl-27559168

ABSTRACT

UNLABELLED: Elucidating patterns of functional synaptic connectivity and deciphering mechanisms of how plasticity influences such connectivity is essential toward understanding brain function. In the mouse olfactory bulb (OB), principal neurons (mitral/tufted cells) make reciprocal connections with local inhibitory interneurons, including granule cells (GCs) and external plexiform layer (EPL) interneurons. Our current understanding of the functional connectivity between these cell types, as well as their experience-dependent plasticity, remains incomplete. By combining acousto-optic deflector-based scanning microscopy and genetically targeted expression of Channelrhodopsin-2, we mapped connections in a cell-type-specific manner between mitral cells (MCs) and GCs or between MCs and EPL interneurons. We found that EPL interneurons form broad patterns of connectivity with MCs, whereas GCs make more restricted connections with MCs. Using an olfactory associative learning paradigm, we found that these circuits displayed differential features of experience-dependent plasticity. Whereas reciprocal connectivity between MCs and EPL interneurons was nonplastic, the connections between GCs and MCs were dynamic and adaptive. Interestingly, experience-dependent plasticity of GCs occurred only in certain stages of neuronal maturation. We show that different interneuron subtypes form distinct connectivity maps and modes of experience-dependent plasticity in the OB, which may reflect their unique functional roles in information processing. SIGNIFICANCE STATEMENT: Deducing how specific interneuron subtypes contribute to normal circuit function requires understanding the dynamics of their connections. In the olfactory bulb (OB), diverse interneuron subtypes vastly outnumber principal excitatory cells. By combining acousto-optic deflector-based scanning microscopy, electrophysiology, and genetically targeted expression of Channelrhodopsin-2, we mapped the functional connectivity between mitral cells (MCs) and OB interneurons in a cell-type-specific manner. We found that, whereas external plexiform layer (EPL) interneurons show broadly distributed patterns of stable connectivity with MCs, adult-born granule cells show dynamic and plastic patterns of synaptic connectivity with task learning. Together, these findings reveal the diverse roles for interneuons within sensory circuits toward information learning and processing.


Subject(s)
Association Learning/physiology , Brain Mapping , Interneurons/physiology , Nerve Net/physiology , Neuronal Plasticity/physiology , Olfactory Bulb/cytology , Analysis of Variance , Animals , Channelrhodopsins , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , In Vitro Techniques , Inhibitory Postsynaptic Potentials/genetics , Inhibitory Postsynaptic Potentials/physiology , Interneurons/classification , LIM-Homeodomain Proteins/genetics , LIM-Homeodomain Proteins/metabolism , Light , Mice , Mice, Transgenic , Microscopy, Confocal , Neural Inhibition/genetics , Neural Inhibition/physiology , Neuronal Plasticity/genetics , Odorants , Optogenetics , Patch-Clamp Techniques , Thy-1 Antigens/genetics , Thy-1 Antigens/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
4.
Neuron ; 55(4): 662-76, 2007 Aug 16.
Article in English | MEDLINE | ID: mdl-17698017

ABSTRACT

Dopamine has been implicated in the modulation of diverse forms of behavioral plasticity, including appetitive learning and addiction. An important challenge is to understand how dopamine's effects at the cellular level alter the properties of neural circuits to modify behavior. In the nematode C. elegans, dopamine modulates habituation of an escape reflex triggered by body touch. In the absence of food, animals habituate more rapidly than in the presence of food; this contextual information about food availability is provided by dopaminergic mechanosensory neurons that sense the presence of bacteria. We find that dopamine alters habituation kinetics by selectively modulating the touch responses of the anterior-body mechanoreceptors; this modulation involves a D1-like dopamine receptor, a Gq/PLC-beta signaling pathway, and calcium release within the touch neurons. Interestingly, the body touch mechanoreceptors can themselves excite the dopamine neurons, forming a positive feedback loop capable of integrating context and experience to modulate mechanosensory attention.


Subject(s)
Caenorhabditis elegans Proteins/physiology , Dopamine/metabolism , Neuronal Plasticity , Neurons, Afferent/physiology , Touch , Animals , Animals, Genetically Modified , Behavior, Animal , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Calcium/metabolism , Escape Reaction/physiology , Habituation, Psychophysiologic/physiology , Models, Biological , Mutation/physiology , Physical Stimulation/methods , Receptors, Dopamine D1/genetics , Receptors, Dopamine D1/metabolism , Signal Transduction/physiology , Statistics, Nonparametric , Time Factors
5.
J Vis Exp ; (133)2018 03 22.
Article in English | MEDLINE | ID: mdl-29630042

ABSTRACT

Olfaction is the predominant sensory modality in mice and influences many important behaviors, including foraging, predator detection, mating, and parenting. Importantly, mice can be trained to associate novel odors with specific behavioral responses to provide insight into olfactory circuit function. This protocol details the procedure for training mice on a Go/No-Go operant learning task. In this approach, mice are trained on hundreds of automated trials daily for 2-4 weeks and can then be tested on novel Go/No-Go odor pairs to assess olfactory discrimination, or be used for studies on how odor learning alters the structure or function of the olfactory circuit. Additionally, the mouse olfactory bulb (OB) features ongoing integration of adult-born neurons. Interestingly, olfactory learning increases both the survival and synaptic connections of these adult-born neurons. Therefore, this protocol can be combined with other biochemical, electrophysiological, and imaging techniques to study learning and activity-dependent factors that mediate neuronal survival and plasticity.


Subject(s)
Smell/physiology , Animals , Discrimination Learning/physiology , Female , Male , Mice , Reproducibility of Results
6.
Nat Neurosci ; 20(2): 189-199, 2017 02.
Article in English | MEDLINE | ID: mdl-28024159

ABSTRACT

Sensory maps are created by networks of neuronal responses that vary with their anatomical position, such that representations of the external world are systematically and topographically organized in the brain. Current understanding from studying excitatory maps is that maps are sculpted and refined throughout development and/or through sensory experience. Investigating the mouse olfactory bulb, where ongoing neurogenesis continually supplies new inhibitory granule cells into existing circuitry, we isolated the development of sensory maps formed by inhibitory networks. Using in vivo calcium imaging of odor responses, we compared functional responses of both maturing and established granule cells. We found that, in contrast to the refinement observed for excitatory maps, inhibitory sensory maps became broader with maturation. However, like excitatory maps, inhibitory sensory maps are sensitive to experience. These data describe the development of an inhibitory sensory map as a network, highlighting the differences from previously described excitatory maps.


Subject(s)
Nerve Net/growth & development , Neurogenesis/physiology , Neurons/physiology , Olfactory Bulb/growth & development , Smell/physiology , Animals , Female , Male , Mice, Transgenic , Odorants/analysis
7.
Dev Cell ; 30(6): 645-59, 2014 Sep 29.
Article in English | MEDLINE | ID: mdl-25199688

ABSTRACT

Neural activity either enhances or impairs de novo synaptogenesis and circuit integration of neurons, but how this activity is mechanistically relayed in the adult brain is largely unknown. Neuropeptide-expressing interneurons are widespread throughout the brain and are key candidates for conveying neural activity downstream via neuromodulatory pathways that are distinct from classical neurotransmission. With the goal of identifying signaling mechanisms that underlie neuronal circuit integration in the adult brain, we have virally traced local corticotropin-releasing hormone (CRH)-expressing inhibitory interneurons with extensive presynaptic inputs onto new neurons that are continuously integrated into the adult rodent olfactory bulb. Local CRH signaling onto adult-born neurons promotes and/or stabilizes chemical synapses in the olfactory bulb, revealing a neuromodulatory mechanism for continued circuit plasticity, synapse formation, and integration of new neurons in the adult brain.


Subject(s)
Corticotropin-Releasing Hormone/metabolism , Interneurons/physiology , Neurogenesis , Synapses/physiology , Animals , Corticotropin-Releasing Hormone/genetics , Interneurons/cytology , Interneurons/metabolism , Mice , Mice, Inbred C57BL , Neuronal Plasticity , Olfactory Bulb/cytology , Olfactory Bulb/growth & development , Olfactory Bulb/metabolism , Synapses/metabolism
8.
Neuron ; 76(6): 1078-90, 2012 Dec 20.
Article in English | MEDLINE | ID: mdl-23259945

ABSTRACT

Brain function is shaped by postnatal experience and vulnerable to disruption of Methyl-CpG-binding protein, Mecp2, in multiple neurodevelopmental disorders. How Mecp2 contributes to the experience-dependent refinement of specific cortical circuits and their impairment remains unknown. We analyzed vision in gene-targeted mice and observed an initial normal development in the absence of Mecp2. Visual acuity then rapidly regressed after postnatal day P35-40 and cortical circuits largely fell silent by P55-60. Enhanced inhibitory gating and an excess of parvalbumin-positive, perisomatic input preceded the loss of vision. Both cortical function and inhibitory hyperconnectivity were strikingly rescued independent of Mecp2 by early sensory deprivation or genetic deletion of the excitatory NMDA receptor subunit, NR2A. Thus, vision is a sensitive biomarker of progressive cortical dysfunction and may guide novel, circuit-based therapies for Mecp2 deficiency.


Subject(s)
Methyl-CpG-Binding Protein 2/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Rett Syndrome/physiopathology , Visual Acuity/physiology , Visual Cortex/physiology , Animals , Disease Models, Animal , Female , Male , Methyl-CpG-Binding Protein 2/genetics , Mice , Mice, Knockout , Nerve Degeneration/pathology , Nerve Degeneration/physiopathology , Neurons/metabolism , Parvalbumins/metabolism , Receptors, N-Methyl-D-Aspartate/genetics , Rett Syndrome/pathology , Vision Tests , Visual Cortex/pathology , Visual Cortex/physiopathology , Visual Pathways/pathology , Visual Pathways/physiology , Visual Pathways/physiopathology
9.
Neuron ; 69(4): 763-79, 2011 Feb 24.
Article in English | MEDLINE | ID: mdl-21338885

ABSTRACT

In the mammalian cerebral cortex, the developmental events governing the integration of excitatory projection neurons and inhibitory interneurons into balanced local circuitry are poorly understood. We report that different subtypes of projection neurons uniquely and differentially determine the laminar distribution of cortical interneurons. We find that in Fezf2⁻/⁻ cortex, the exclusive absence of subcerebral projection neurons and their replacement by callosal projection neurons cause distinctly abnormal lamination of interneurons and altered GABAergic inhibition. In addition, experimental generation of either corticofugal neurons or callosal neurons below the cortex is sufficient to recruit cortical interneurons to these ectopic locations. Strikingly, the identity of the projection neurons generated, rather than strictly their birthdate, determines the specific types of interneurons recruited. These data demonstrate that in the neocortex individual populations of projection neurons cell-extrinsically control the laminar fate of interneurons and the assembly of local inhibitory circuitry.


Subject(s)
Cerebral Cortex/cytology , Cerebral Cortex/growth & development , Gene Expression Regulation, Developmental/physiology , Interneurons/physiology , Nerve Net/physiology , Neural Inhibition/physiology , Age Factors , Animals , Animals, Newborn , Cell Count , Cell Movement/genetics , Corpus Callosum/cytology , Corpus Callosum/growth & development , DNA-Binding Proteins/deficiency , Electric Stimulation , Electroporation/methods , Embryo, Mammalian , Female , Functional Laterality/genetics , Gene Expression Regulation, Developmental/genetics , Glutamate Decarboxylase/genetics , Green Fluorescent Proteins/genetics , Membrane Potentials/genetics , Mice , Mice, Transgenic , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neural Pathways/physiology , Neurons/classification , Neurons/physiology , Patch-Clamp Techniques , Pregnancy
10.
J Neurodev Disord ; 1(2): 172-81, 2009 Jun.
Article in English | MEDLINE | ID: mdl-20664807

ABSTRACT

UNLABELLED: One unifying explanation for the complexity of Autism Spectrum Disorders (ASD) may lie in the disruption of excitatory/inhibitory (E/I) circuit balance during critical periods of development. We examined whether Parvalbumin (PV)-positive inhibitory neurons, which normally drive experience-dependent circuit refinement (Hensch Nat Rev Neurosci 6:877-888, 1), are disrupted across heterogeneous ASD mouse models. We performed a meta-analysis of PV expression in previously published ASD mouse models and analyzed two additional models, reflecting an embryonic chemical insult (prenatal valproate, VPA) or single-gene mutation identified in human patients (Neuroligin-3, NL-3 R451C). PV-cells were reduced in the neocortex across multiple ASD mouse models. In striking contrast to controls, both VPA and NL-3 mouse models exhibited an asymmetric PV-cell reduction across hemispheres in parietal and occipital cortices (but not the underlying area CA1). ASD mouse models may share a PV-circuit disruption, providing new insight into circuit development and potential prevention by treatment of autism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11689-009-9023-x) contains supplementary material, which is available to authorized users.

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