scholarly journals Reduced GluN1 in mouse dentate gyrus is associated with CA3 hyperactivity and psychosis-like behaviors

2018 ◽  
Vol 25 (11) ◽  
pp. 2832-2843 ◽  
Author(s):  
Amir Segev ◽  
Masaya Yanagi ◽  
Daniel Scott ◽  
Sarah A. Southcott ◽  
Jacob M. Lister ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Basolateral Amygdala ◽  
Pyramidal Neurons ◽  
Mossy Fibers ◽  
Model Systems ◽  
Memory Processing ◽  
Hippocampal Subfields ◽  
Whole Cell Patch Clamp ◽  
Hippocampal Activity

Abstract Recent findings from in vivo-imaging and human post-mortem tissue studies in schizophrenic psychosis (SzP), have demonstrated functional and molecular changes in hippocampal subfields that can be associated with hippocampal hyperexcitability. In this study, we used a subfield-specific GluN1 knockout mouse with a disease-like molecular perturbation expressed only in hippocampal dentate gyrus (DG) and assessed its association with hippocampal physiology and psychosis-like behaviors. First, we used whole-cell patch-clamp recordings to measure the physiological changes in hippocampal subfields and cFos immunohistochemistry to examine cellular excitability. DG-GluN1 KO mice show CA3 cellular hyperactivity, detected using two approaches: (1) increased excitatory glutamate transmission at mossy fibers (MF)-CA3 synapses, and (2) an increased number of cFos-activated pyramidal neurons in CA3, an outcome that appears to project downstream to CA1 and basolateral amygdala (BLA). Furthermore, we examined psychosis-like behaviors and pathological memory processing; these show an increase in fear conditioning (FC), a reduction in prepulse inhibition (PPI) in the KO animal, along with a deterioration in memory accuracy with Morris Water Maze (MWM) and reduced social memory (SM). Moreover, with DREADD vectors, we demonstrate a remarkably similar behavioral profile when we induce CA3 hyperactivity. These hippocampal subfield changes could provide the basis for the observed increase in human hippocampal activity in SzP, based on the shared DG-specific GluN1 reduction. With further characterization, these animal model systems may serve as targets to test psychosis mechanisms related to hippocampus and assess potential hippocampus-directed treatments.

scholarly journals Amygdala inputs drive feedforward inhibition in the medial prefrontal cortex

2013 ◽  
Vol 110 (1) ◽  
pp. 221-229 ◽  
Author(s):  
Jonathan Dilgen ◽  
Hugo A. Tejeda ◽  
Patricio O'Donnell
Keyword(s):  
Prefrontal Cortex ◽  
Basolateral Amygdala ◽  
Pyramidal Neurons ◽  
Reversal Potential ◽  
Intracellular Recordings ◽  
Action Potential Firing ◽  
Gaba A ◽  
Potential Firing ◽  
Feedforward Inhibition

Although interactions between the amygdala and prefrontal cortex (PFC) are critical for emotional guidance of behavior, the manner in which amygdala affects PFC function is not clear. Whereas basolateral amygdala (BLA) output neurons exhibit many characteristics associated with excitatory neurotransmission, BLA stimulation typically inhibits PFC cell firing. This apparent discrepancy could be explained if local PFC inhibitory interneurons were activated by BLA inputs. Here, we used in vivo juxtacellular and intracellular recordings in anesthetized rats to investigate whether BLA inputs evoke feedforward inhibition in the PFC. Juxtacellular recordings revealed that BLA stimulation evoked action potentials in PFC interneurons and silenced most pyramidal neurons. Intracellular recordings from PFC pyramidal neurons showed depolarizing postsynaptic potentials, with multiple components evoked by BLA stimulation. These responses exhibited a relatively negative reversal potential (Erev), suggesting the contribution of a chloride component. Intracellular administration or pressure ejection of the GABA-A antagonist picrotoxin resulted in action-potential firing during the BLA-evoked response, which had a more depolarized Erev. These results suggest that BLA stimulation engages a powerful inhibitory mechanism within the PFC mediated by local circuit interneurons.

scholarly journals Downregulation of CDK5 Signaling In the Dorsal Striatum Alters Striatal Microcircuits and Perturbs Circadian Behavior in Mice

2021 ◽  
Author(s):  
Hu Zhou ◽  
Jingxin Zhang ◽  
Huaxiang Shi ◽  
Pengfei Li ◽  
Xin Sui ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Basolateral Amygdala ◽  
Fluorescent Protein ◽  
Critical Role ◽  
Motor Impairment ◽  
Dorsal Striatum ◽  
Thalamic Nuclei ◽  
Whole Cell Patch Clamp ◽  
Green Fluorescent

Abstract Dysfunction of striatal dopaminergic circuits has been implicated in motor impairment as well as in Parkinson’s disease (PD)-related circadian perturbations that may represent an early prodromal marker of PD. Cyclin-dependent kinase 5 (CDK5) acts negatively on dopamine (DA) signaling in the striatum, suggesting a critical role in circadian and sleep disorders. Here, we used CRISPR/Cas9 gene editing to produce dorsal striatum (DS)-specific knockdown (KD) of the Cdk5 gene in mice (referred to as DS-CDK5-KD mice) to investigate its role in vivo. DS-CDK5-KD mice exhibited deficits in locomotor activity and disturbances in daily rest/activity cycles. Additionally, Golgi staining of neurons in the DS revealed that Cdk5 deletion caused a reduction in dendrite length and functional synapses, which was confirmed by significant downregulation of MAP2, PSD95 and synapsin I. Correlated with this, DS-CDK5-KD mice displayed reduced phosphorylation of Tau at Thr181. Furthermore, whole-cell patch-clamp recordings of green fluorescent protein (GFP)-tagged neurons in the striatum of DS-CDK5-KD mice revealed a decrease in the frequency of spontaneous inhibitory post-synaptic currents and an alteration of the excitatory/inhibitory synaptic balance. Notably, anterograde labeling showed that CDK5 knockdown in the DS disrupted long-range projections to the secondary motor cortex, dorsal and ventral thalamic nuclei, and the basolateral amygdala, which are involved in the regulation of motor and circadian rhythms in the brain. These findings support a critical role of CDK5 in the DS in maintaining the striatal neural circuitry underlying motor and circadian rhythms related to PD.

scholarly journals Kv1.1 contributes to a rapid homeostatic plasticity of intrinsic excitability in CA1 pyramidal neurons in vivo

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Peter James Morgan ◽  
Romain Bourboulou ◽  
Caroline Filippi ◽  
Julie Koenig-Gambini ◽  
Jérôme Epsztein
Keyword(s):  
Pyramidal Neurons ◽  
Place Cells ◽  
Homeostatic Plasticity ◽  
Intrinsic Excitability ◽  
Memory Interference ◽  
Ca1 Pyramidal Neurons ◽  
Whole Cell Patch Clamp ◽  
Activity Dependent

In area CA1 of the hippocampus, the selection of place cells to represent a new environment is biased towards neurons with higher excitability. However, different environments are represented by orthogonal cell ensembles, suggesting that regulatory mechanisms exist. Activity-dependent plasticity of intrinsic excitability, as observed in vitro, is an attractive candidate. Here, using whole-cell patch-clamp recordings of CA1 pyramidal neurons in anesthetized rats, we have examined how inducing theta-bursts of action potentials affects their intrinsic excitability over time. We observed a long-lasting, homeostatic depression of intrinsic excitability which commenced within minutes, and, in contrast to in vitro observations, was not mediated by dendritic Ih. Instead, it was attenuated by the Kv1.1 channel blocker dendrotoxin K, suggesting an axonal origin. Analysis of place cells’ out-of-field firing in mice navigating in virtual reality further revealed an experience-dependent reduction consistent with decreased excitability. We propose that this mechanism could reduce memory interference.

scholarly journals Spike Frequency Adaptation and Neocortical Rhythms

2002 ◽  
Vol 88 (2) ◽  
pp. 761-770 ◽  
Author(s):  
Galit Fuhrmann ◽  
Henry Markram ◽  
Misha Tsodyks
Keyword(s):  
Firing Rate ◽  
Pyramidal Neurons ◽  
Spike Frequency ◽  
Spike Frequency Adaptation ◽  
Patch Clamp Technique ◽  
Response Characteristics ◽  
Frequency Adaptation ◽  
Whole Cell Patch Clamp ◽  
The Mean

Spike-frequency adaptation in neocortical pyramidal neurons was examined using the whole cell patch-clamp technique and a phenomenological model of neuronal activity. Noisy current was injected to reproduce the irregular firing typically observed under in vivo conditions. The response was quantified by computing the poststimulus histogram (PSTH). To simulate the spiking activity of a pyramidal neuron, we considered an integrate-and-fire model to which an adaptation current was added. A simplified model for the mean firing rate of an adapting neuron under noisy conditions is also presented. The mean firing rate model provides a good fit to both experimental and simulation PSTHs and may therefore be used to study the response characteristics of adapting neurons to various input currents. The models enable identification of the relevant parameters of adaptation that determine the shape of the PSTH and allow the computation of the response to any change in injected current. The results suggest that spike frequency adaptation determines a preferred frequency of stimulation for which the phase delay of a neuron's activity relative to an oscillatory input is zero. Simulations show that the preferred frequency of single neurons dictates the frequency of emergent population rhythms in large networks of adapting neurons. Adaptation could therefore be one of the crucial factors in setting the frequency of population rhythms in the neocortex.

scholarly journals Distinct Subtypes of Cholecystokinin (CCK)-Containing Interneurons of the Basolateral Amygdala Identified Using a CCK Promoter-Specific Lentivirus

2009 ◽  
Vol 101 (3) ◽  
pp. 1494-1506 ◽  
Author(s):  
Aaron M. Jasnow ◽  
Kerry J. Ressler ◽  
Sayamwong E. Hammack ◽  
Jasmeer P. Chhatwal ◽  
Donald G. Rainnie
Keyword(s):  
Basolateral Amygdala ◽  
Function Analysis ◽  
Hierarchical Cluster ◽  
Heterogeneous Population ◽  
Membrane Properties ◽  
Patch Clamp Recording ◽  
Whole Cell Patch Clamp ◽  
Physiological Properties ◽  
Current Clamp Mode

The basolateral amygdala (BLA) is critical for the formation of emotional memories. Little is known about the physiological properties of BLA interneurons, which can be divided into four subtypes based on their immunocytochemical profiles. Cholecystokinin (CCK) interneurons play critical roles in feedforward inhibition and behavioral fear responses. Evidence suggests that interneurons within a subgroup can display heterogeneous physiological properties. However, little is known about the physiological properties of CCK interneurons in the BLA and/or whether they represent a homogeneous or heterogeneous population. To address this question, we generated a lentivirus-expressing GFP under the control of the CCK promoter to identify CCK neurons in vivo. We combined this with whole cell patch-clamp recording techniques to examine the physiological properties of CCK-containing interneurons of the rat BLA. Here, we describe the physiological properties of 57 cells recorded in current-clamp mode; we used hierarchical cluster and discriminant function analysis to demonstrate that CCK interneurons can be segregated into three distinct subtypes (I, II, III) based on their passive and active membrane properties. Additionally, Type II neurons could be further separated into adapting and nonadapting types based on their rates of spike frequency adaptation. These data suggest that CCK interneurons of the BLA are a heterogeneous population and may be functionally distinct subpopulations that differentially contribute to the processing of emotionally salient stimuli.

scholarly journals A synaptic novelty signal in the dentate gyrus supports switching hippocampal attractor networks from generalization to discrimination

2021 ◽  
Author(s):  
Ruy Gómez-Ocádiz ◽  
Massimiliano Trippa ◽  
Lorenzo Posani ◽  
Simona Cocco ◽  
Rémi Monasson ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Virtual Environments ◽  
Acetylcholine Receptors ◽  
Granule Cells ◽  
Memory Formation ◽  
Synaptic Response ◽  
Population Activity ◽  
Attractor Networks ◽  
Whole Cell Patch Clamp

AbstractEpisodic memory formation and recall are complementary processes that put conflicting requirements on neuronal computations in the hippocampus. How this challenge is resolved in hippocampal circuits is unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice navigating in familiar and novel virtual environments. We find that granule cells consistently show a small transient depolarization of their membrane potential upon transition to a novel environment. This synaptic novelty signal is sensitive to local application of atropine, indicating that it depends on metabotropic acetylcholine receptors. A computational model suggests that the observed transient synaptic response to novel environments may lead to a bias in the granule cell population activity, which can in turn drive the downstream attractor networks to a new state, thereby favoring the switch from generalization to discrimination when faced with novelty. Such a novelty-driven cholinergic switch may enable flexible encoding of new memories while preserving stable retrieval of familiar ones.

scholarly journals Magnetic Resonance Elastography of Human Hippocampal Subfields: CA3-Dentate Gyrus Viscoelasticity Predicts Relational Memory Accuracy

2020 ◽  
Vol 32 (9) ◽  
pp. 1704-1713
Author(s):  
Ana M. Daugherty ◽  
Hillary D. Schwarb ◽  
Matthew D. J. McGarry ◽  
Curtis L. Johnson ◽  
Neal J. Cohen
Keyword(s):  
Magnetic Resonance ◽  
Dentate Gyrus ◽  
Damping Ratio ◽  
Memory Function ◽  
Magnetic Resonance Elastography ◽  
Elastic Behavior ◽  
Relational Memory ◽  
Hippocampal Subfields ◽  
Memory Accuracy

The hippocampus is necessary for binding and reconstituting information in relational memory. These essential memory functions are supported by the distinct cytoarchitecture of the hippocampal subfields. Magnetic resonance elastography is an emerging tool that provides sensitive estimates of microstructure vis-à-vis tissue mechanical properties. Here, we report the first in vivo study of human hippocampal subfield viscoelastic stiffness and damping ratio. Stiffness describes resistance of a viscoelastic tissue to a stress and is thought to reflect the relative composition of tissue at the microscale; damping ratio describes relative viscous-to-elastic behavior and is thought to generally reflect microstructural organization. Measures from the subiculum (combined with presubiculum and parasubiculum), cornu ammonis (CA) 1–2, and CA3-dentate gyrus (CA3-DG) were collected in a sample of healthy, cognitively normal men ( n = 20, age = 18–33 years). In line with known cytoarchitecture, the subiculum demonstrated the lowest damping ratio, followed by CA3-DG and then combined CA1–CA2. Moreover, damping ratio of the CA3-DG—potentially reflective of number of cells and their connections—predicted relational memory accuracy and alone replicated most of the variance in performance that was explained by the whole hippocampus. Stiffness did not differentiate the hippocampal subfields and was unrelated to task performance in this sample. Viscoelasticity measured with magnetic resonance elastography appears to be sensitive to microstructural properties relevant to specific memory function, even in healthy younger adults, and is a promising tool for future studies of hippocampal structure in aging and related diseases.

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