Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 13 de 13
Filter
Add more filters










Publication year range
1.
bioRxiv ; 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38979308

ABSTRACT

Animals perform innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance. The cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However, little is known about how this brain area gives rise to behaviors of opposing motivational valence. Here, we sought to define the circuit features of plCoA that give rise to innate olfactory behaviors of valence. We characterized the physiology, gene expression, and projections of this structure, identifying a divergent, topographic organization that selectively controls innate attraction and avoidance to odor. First, we examined odor-evoked responses in these areas and found sparse encoding of odor identity, but not valence. We next considered a topographic organization and found that optogenetic stimulation of the anterior and posterior domains of plCoA elicits attraction and avoidance, respectively, suggesting a functional axis for valence. Using single cell and spatial RNA sequencing, we identified the molecular cell types in plCoA, revealing an anteroposterior gradient in cell types, whereby anterior glutamatergic neurons preferentially express Slc17a6 and posterior neurons express Slc17a7. Activation of these respective cell types recapitulates appetitive and aversive valence behaviors, and chemogenetic inhibition reveals partial necessity for valence responses to innate appetitive or aversive odors. Finally, we identified topographically organized circuits defined by projections, whereby anterior neurons preferentially project to medial amygdala, and posterior neurons preferentially project to nucleus accumbens, which are respectively sufficient and necessary for innate negative and positive olfactory valence. Together, these data advance our understanding of how the olfactory system generates stereotypic, hardwired attraction and avoidance, and supports a model whereby distinct, topographically distributed plCoA populations direct innate olfactory valence responses by signaling to divergent valence-specific targets, linking upstream olfactory identity to downstream valence behaviors, through a population code. This represents a novel circuit motif in which valence encoding is represented not by the firing properties of individual neurons, but by population level identity encoding that is routed through divergent targets to mediate distinct valence.

2.
Psychopharmacology (Berl) ; 240(3): 477-499, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36522481

ABSTRACT

RATIONALE: The basolateral amygdala (BLA) and medial geniculate nucleus of the thalamus (MGN) have both been shown to be necessary for the formation of associative learning. While the role that the BLA plays in this process has long been emphasized, the MGN has been less well-studied and surrounded by debate regarding whether the relay of sensory information is active or passive. OBJECTIVES: We seek to understand the role the MGN has within the thalamoamgydala circuit in the formation of associative learning. METHODS: Here, we use optogenetics and in vivo electrophysiological recordings to dissect the MGN-BLA circuit and explore the specific subpopulations for evidence of learning and synthesis of information that could impact downstream BLA encoding. We employ various machine learning techniques to investigate function within neural subpopulations. We introduce a novel method to investigate tonic changes across trial-by-trial structure, which offers an alternative approach to traditional trial-averaging techniques. RESULTS: We find that the MGN appears to encode arousal but not valence, unlike the BLA which encodes for both. We find that the MGN and the BLA appear to react differently to expected and unexpected outcomes; the BLA biased responses toward reward prediction error and the MGN focused on anticipated punishment. We uncover evidence of tonic changes by visualizing changes across trials during inter-trial intervals (baseline epochs) for a subset of cells. CONCLUSION: We conclude that the MGN-BLA projector population acts as both filter and transferer of information by relaying information about the salience of cues to the amygdala, but these signals are not valence-specified.


Subject(s)
Amygdala , Basolateral Nuclear Complex , Amygdala/physiology , Thalamus , Basolateral Nuclear Complex/physiology , Conditioning, Classical/physiology , Arousal
3.
Elife ; 112022 06 06.
Article in English | MEDLINE | ID: mdl-35662394

ABSTRACT

LRRTMs are postsynaptic cell adhesion proteins that have region-restricted expression in the brain. To determine their role in the molecular organization of synapses in vivo, we studied synapse development and plasticity in hippocampal neuronal circuits in mice lacking both Lrrtm1 and Lrrtm2. We found that LRRTM1 and LRRTM2 regulate the density and morphological integrity of excitatory synapses on CA1 pyramidal neurons in the developing brain but are not essential for these roles in the mature circuit. Further, they are required for long-term-potentiation in the CA3-CA1 pathway and the dentate gyrus, and for enduring fear memory in both the developing and mature brain. Our data show that LRRTM1 and LRRTM2 regulate synapse development and function in a cell-type and developmental-stage-specific manner, and thereby contribute to the fine-tuning of hippocampal circuit connectivity and plasticity.


Subject(s)
Membrane Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neural Cell Adhesion Molecules , Animals , Hippocampus/physiology , Long-Term Potentiation/physiology , Mice , Neural Cell Adhesion Molecules/metabolism , Synapses/physiology
4.
Nature ; 603(7902): 667-671, 2022 03.
Article in English | MEDLINE | ID: mdl-35296862

ABSTRACT

Most social species self-organize into dominance hierarchies1,2, which decreases aggression and conserves energy3,4, but it is not clear how individuals know their social rank. We have only begun to learn how the brain represents social rank5-9 and guides behaviour on the basis of this representation. The medial prefrontal cortex (mPFC) is involved in social dominance in rodents7,8 and humans10,11. Yet, precisely how the mPFC encodes relative social rank and which circuits mediate this computation is not known. We developed a social competition assay in which mice compete for rewards, as well as a computer vision tool (AlphaTracker) to track multiple, unmarked animals. A hidden Markov model combined with generalized linear models was able to decode social competition behaviour from mPFC ensemble activity. Population dynamics in the mPFC predicted social rank and competitive success. Finally, we demonstrate that mPFC cells that project to the lateral hypothalamus promote dominance behaviour during reward competition. Thus, we reveal a cortico-hypothalamic circuit by which the mPFC exerts top-down modulation of social dominance.


Subject(s)
Hypothalamus , Prefrontal Cortex , Animals , Hypothalamic Area, Lateral , Mice , Reward , Social Behavior
5.
Nat Neurosci ; 21(10): 1296-1297, 2018 10.
Article in English | MEDLINE | ID: mdl-30258236
6.
Cell ; 173(6): 1329-1342.e18, 2018 05 31.
Article in English | MEDLINE | ID: mdl-29731170

ABSTRACT

Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC→BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC→BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC→BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this routing of information is critically instructive for observational fear conditioning. VIDEO ABSTRACT.


Subject(s)
Basolateral Nuclear Complex/physiology , Cerebral Cortex/physiology , Learning/physiology , Amygdala/physiology , Animals , Behavior, Animal , Conditioning, Classical , Electrophysiological Phenomena , Fear , Light , Male , Memory/physiology , Mice , Neural Pathways/physiology , Neurons/physiology , Optogenetics , Prefrontal Cortex/physiology
7.
Nat Neurosci ; 20(4): 540-549, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28192395

ABSTRACT

Drugs of abuse alter synaptic connections in the reward circuitry of the brain, which leads to long-lasting behavioral changes that underlie addiction. Here we show that cadherin adhesion molecules play a critical role in mediating synaptic plasticity and behavioral changes driven by cocaine. We demonstrate that cadherin is essential for long-term potentiation in the ventral tegmental area and is recruited to the synaptic membranes of excitatory synapses onto dopaminergic neurons following cocaine-mediated behavioral conditioning. Furthermore, we show that stabilization of cadherin at the membrane of these synapses blocks cocaine-induced synaptic plasticity, leading to a reduction in conditioned place preference induced by cocaine. Our findings identify cadherins and associated molecules as targets of interest for understanding pathological plasticity associated with addiction.


Subject(s)
Cadherins/physiology , Cocaine/pharmacology , Conditioning, Psychological/physiology , Neuronal Plasticity/physiology , Ventral Tegmental Area/physiology , Animals , Cadherins/metabolism , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/physiology , Long-Term Potentiation/drug effects , Long-Term Potentiation/physiology , Male , Mice , Mice, Transgenic , Neuronal Plasticity/drug effects , Receptors, AMPA/metabolism , Synapses/physiology , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/metabolism
8.
Proc Natl Acad Sci U S A ; 113(9): 2520-5, 2016 Mar 01.
Article in English | MEDLINE | ID: mdl-26884159

ABSTRACT

In an environment with easy access to highly palatable and energy-dense food, food-related cues drive food-seeking regardless of satiety, an effect that can lead to obesity. The ventral tegmental area (VTA) and its mesolimbic projections are critical structures involved in the learning of environmental cues used to predict motivationally relevant outcomes. Priming effects of food-related advertising and consumption of palatable food can drive food intake. However, the mechanism by which this effect occurs, and whether these priming effects last days after consumption, is unknown. Here, we demonstrate that short-term consumption of palatable food can prime future food approach behaviors and food intake. This effect is mediated by the strengthening of excitatory synaptic transmission onto dopamine neurons that is initially offset by a transient increase in endocannabinoid tone, but lasts days after an initial 24-h exposure to sweetened high-fat food (SHF). This enhanced synaptic strength is mediated by a long-lasting increase in excitatory synaptic density onto VTA dopamine neurons. Administration of insulin into the VTA, which suppresses excitatory synaptic transmission onto dopamine neurons, can abolish food approach behaviors and food intake observed days after 24-h access to SHF. These results suggest that even a short-term exposure to palatable foods can drive future feeding behavior by "rewiring" mesolimbic dopamine neurons.


Subject(s)
Feeding Behavior , Synapses , Ventral Tegmental Area/physiology , Animals , Male , Mice , Mice, Inbred C57BL
9.
Proc Natl Acad Sci U S A ; 111(23): 8631-6, 2014 Jun 10.
Article in English | MEDLINE | ID: mdl-24912177

ABSTRACT

The cadherin/ß-catenin adhesion complex is a key mediator of the bidirectional changes in synapse strength which are believed to underlie complex learning and memory. In the present study, we demonstrate that stabilization of ß-catenin in the hippocampus of adult mice results in significant impairments in cognitive flexibility and spatial reversal learning, including impaired extinction during the reversal phase of the Morris water maze and deficits in a delayed nonmatch to place T-maze task. In accordance with these deficits, ß-catenin stabilization was found to abolish long-term depression by stabilizing cadherin at the synaptic membrane and impairing AMPA receptor endocytosis, while leaving basal synaptic transmission and long-term potentiation unaffected. These results demonstrate that the ß-catenin/cadherin adhesion complex plays an important role in learning and memory and that aberrant increases in synaptic adhesion can have deleterious effects on cognitive function.


Subject(s)
Cognition/physiology , Hippocampus/physiopathology , Long-Term Synaptic Depression/physiology , beta Catenin/metabolism , Animals , Cadherins/metabolism , Endocytosis/genetics , Endocytosis/physiology , Female , Hippocampus/metabolism , Hippocampus/ultrastructure , Immunoblotting , Long-Term Synaptic Depression/drug effects , Long-Term Synaptic Depression/genetics , Male , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microscopy, Immunoelectron , N-Methylaspartate/pharmacology , Neurons/metabolism , Neurons/physiology , Protein Binding , Receptors, AMPA/metabolism , Synapses/metabolism , Synapses/physiology , Synaptosomes/metabolism , beta Catenin/genetics
10.
J Cell Sci ; 126(Pt 23): 5412-21, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24046442

ABSTRACT

The secreted growth factor progranulin (PGRN) has been shown to be important for regulating neuronal survival and outgrowth, as well as synapse formation and function. Mutations in the PGRN gene that result in PGRN haploinsufficiency have been identified as a major cause of frontotemporal dementia (FTD). Here we demonstrate that PGRN is colocalized with dense-core vesicle markers and is co-transported with brain-derived neurotrophic factor (BDNF) within axons and dendrites of cultured hippocampal neurons in both anterograde and retrograde directions. We also show that PGRN is secreted in an activity-dependent manner from synaptic and extrasynaptic sites, and that the temporal profiles of secretion are distinct in axons and dendrites. Neuronal activity is also shown to increase the recruitment of PGRN to synapses and to enhance the density of PGRN clusters along axons. Finally, treatment of neurons with recombinant PGRN is shown to increase synapse density, while decreasing the size of the presynaptic compartment and specifically the number of synaptic vesicles per synapse. Together, this indicates that activity-dependent secretion of PGRN can regulate synapse number and structure.


Subject(s)
Axons/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Dendrites/metabolism , Hippocampus/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Protein Precursors/metabolism , Animals , Brain-Derived Neurotrophic Factor/genetics , Embryo, Mammalian , Gene Expression , Hippocampus/cytology , Humans , Intercellular Signaling Peptides and Proteins/genetics , Progranulins , Protein Precursors/genetics , Protein Transport , Rats , Rats, Sprague-Dawley , Secretory Vesicles/metabolism , Synapses/metabolism , Synaptic Vesicles/metabolism
11.
J Neurosci ; 31(31): 11126-32, 2011 Aug 03.
Article in English | MEDLINE | ID: mdl-21813674

ABSTRACT

Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene (GRN) that lead to progranulin (PGRN) haploinsufficiency. Thus far, our understanding of the effects of PGRN depletion in the brain has been derived from investigation of gross pathology, and more detailed analyses of cellular function have been lacking. We report that knocking down PGRN levels in rat primary hippocampal cultures reduces neural connectivity by decreasing neuronal arborization and length as well as synapse density. Despite this, the number of synaptic vesicles per synapse and the frequency of mEPSCs are increased in PGRN knockdown cells, suggesting an increase in the probability of release at remaining synapses. Interestingly, we demonstrate that the number of vesicles per synapse is also increased in postmortem brain sections from FTD patients with PGRN haploinsufficiency, relative to controls. Our observations show that PGRN knockdown severely alters neuronal connectivity in vitro and that the synaptic vesicle phenotype observed in culture is consistent with that observed in the hippocampus of FTD patients.


Subject(s)
Excitatory Postsynaptic Potentials/physiology , Frontotemporal Dementia/pathology , Intercellular Signaling Peptides and Proteins/deficiency , Neurons/physiology , Synapses/physiology , Aged , Analysis of Variance , Animals , Cells, Cultured , Dendrites/ultrastructure , Disks Large Homolog 4 Protein , Embryo, Mammalian , Excitatory Postsynaptic Potentials/genetics , Female , Frontotemporal Dementia/genetics , Green Fluorescent Proteins/genetics , Guanylate Kinases/genetics , Hippocampus/cytology , Humans , In Situ Nick-End Labeling/methods , Intercellular Signaling Peptides and Proteins/genetics , Luminescent Proteins/genetics , Male , Membrane Proteins/genetics , Microscopy, Electron, Transmission , Mutation , Pyridinium Compounds/metabolism , Quaternary Ammonium Compounds/metabolism , RNA, Small Interfering/metabolism , Rats , Receptors, AMPA/metabolism , Synapses/genetics , Synapses/ultrastructure , Synaptic Vesicles/genetics , Synaptic Vesicles/physiology , Synaptic Vesicles/ultrastructure , Synaptophysin/metabolism , Tetrazolium Salts , Thiazoles , Transfection/methods
12.
Mol Biol Cell ; 22(13): 2246-57, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21551074

ABSTRACT

Subtle changes in cellular and extracellular pH within the physiological range have profound impacts on synaptic activities. However, the molecular mechanisms underlying local pH regulation at synapses and their influence on synaptic structures have not been elucidated. Dendritic spines undergo dynamic structural changes in response to neuronal activation, which contributes to induction and long-term maintenance of synaptic plasticity. Although previous studies have indicated the importance of cytoskeletal rearrangement, vesicular trafficking, cell signaling, and adhesion in this process, much less is known about the involvement of ion transporters. In this study we demonstrate that N-methyl-D-aspartate (NMDA) receptor activation causes recruitment of the brain-enriched Na(+)/H(+) exchanger NHE5 from endosomes to the plasma membrane. Concomitantly, real-time imaging of green fluorescent protein-tagged NHE5 revealed that NMDA receptor activation triggers redistribution of NHE5 to the spine head. We further show that neuronal activation causes alkalinization of dendritic spines following the initial acidification, and suppression of NHE5 significantly retards the activity-induced alkalinization. Perturbation of NHE5 function induces spontaneous spine growth, which is reversed by inhibition of NMDA receptors. In contrast, overexpression of NHE5 inhibits spine growth in response to neuronal activity. We propose that NHE5 constrains activity-dependent dendritic spine growth via a novel, pH-based negative-feedback mechanism.


Subject(s)
Brain/metabolism , Dendritic Spines/metabolism , Sodium-Hydrogen Exchangers/metabolism , Animals , CHO Cells , Cell Membrane/metabolism , Cells, Cultured , Cricetinae , Cricetulus , Endosomes/metabolism , Humans , Hydrogen-Ion Concentration , Ion Transport , Neurons/metabolism , Protein Transport , Rats , Receptors, N-Methyl-D-Aspartate/metabolism , Sodium-Hydrogen Exchangers/genetics , Synapses/metabolism
13.
Biochim Biophys Acta ; 1769(1): 49-60, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17198736

ABSTRACT

The coding region of c-myc mRNA encompassing the coding region determinant (CRD) nucleotides (nts) 1705-1792 is critical in regulating c-myc mRNA stability. This is in part due to the susceptibility of c-myc CRD RNA to attack by an endoribonuclease. We have previously purified and characterized a mammalian endoribonuclease that cleaves c-myc CRD RNA in vitro. This enzyme is tentatively identified as a 35 kDa RNase1-like endonuclease. In an effort to understand the sequence and secondary structure requirements for RNA cleavage by this enzyme, we have determined the secondary structure of the c-myc CRD RNA nts 1705-1792 using RNase probing technique. The secondary structure of c-myc CRD RNA possesses five stems; two of which contain 4 base pairs (stems I and V) and three consisting of 3 base pairs (stems II, III, and IV). Endonucleolytic assays using the c-myc CRD and several c-myc CRD mutants as substrates led to the following conclusions: (i) the enzyme prefers to cleave in between the dinucleotides UA, CA, and UG in single-stranded regions; (ii) the enzyme is more specific towards UA dinucleotides. These properties further distinguish the enzyme from previously described mammalian endonuclease that cleaves c-myc mRNA in vitro.


Subject(s)
Endoribonucleases/metabolism , Genes, myc , RNA, Messenger/chemistry , Base Sequence , Humans , Molecular Sequence Data , Molecular Structure , Open Reading Frames
SELECTION OF CITATIONS
SEARCH DETAIL
...