IGF-1 facilitates extinction of conditioned fear

SUMMARYInsulin-like growth factor-1 (IGF-1) plays a key role in synaptic plasticity, degenerative diseases, spatial learning, and anxiety-like behavioral processes. While IGF-1 regulates neuronal activity in many areas of the brain, its effect on synaptic plasticity and animal behavior dependent on the prefrontal cortex remain unexplored. Here, we show that IGF-1 induces a long-lasting depression of the medium and slow post-spike afterhyperpolarization (mAHP and sAHP), increasing the excitability of layer 5 pyramidal neurons of the infralimbic cortex. Besides, IGF-1 mediates a long-term depression of both inhibitory and excitatory synaptic transmission that results in a longterm potentiation of the postsynaptic potentials. We demonstrate that these synaptic and intrinsic regulatory processes mediated by IGF-1 favor the fear extinction memory. These results show novel functional consequences of IGF-1 signaling on animal behavior tasks dependent on the prefrontal cortex, revealing IGF-1 as a key element in the control of the fear extinction memory.Impact StatementIGF-1 modulates the neuronal firing and synaptic plasticity in infralimbic cortex, favoring the extinction memory

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IGF-1 facilitates extinction of conditioned fear

eLife ◽

10.7554/elife.67267 ◽

2021 ◽

Vol 10 ◽

Author(s):

Laura E Maglio ◽

José A Noriega-Prieto ◽

Irene B Maroto ◽

Jesús Martin-Cortecero ◽

Antonio Muñoz-Callejas ◽

...

Keyword(s):

Synaptic Plasticity ◽

Synaptic Transmission ◽

Pyramidal Neurons ◽

Conditioned Fear ◽

Long Term Potentiation ◽

Fear Extinction ◽

Neuronal Firing ◽

Term Potentiation ◽

Extinction Memory

Insulin-like growth factor-1 (IGF-1) plays a key role in synaptic plasticity, spatial learning and anxiety-like behavioral processes. While IGF-1 regulates neuronal firing and synaptic transmission in many areas of the central nervous system, its signaling and consequences on excitability, synaptic plasticity, and animal behavior dependent on the prefrontal cortex remain unexplored. Here, we show that IGF-1 induces a long-lasting depression of the medium and slow post-spike afterhyperpolarization (mAHP and sAHP), increasing the excitability of layer 5 pyramidal neurons of the rat infralimbic cortex. Besides, IGF-1 mediates a presynaptic long-term depression of both inhibitory and excitatory synaptic transmission in these neurons. The net effect of this IGF-1 mediated synaptic plasticity is a long-term potentiation of the postsynaptic potentials. Moreover, we demonstrate that IGF-1 favors the fear extinction memory. These results show novel functional consequences of IGF-1 signaling, revealing IGF-1 as a key element in the control of the fear extinction memory.

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Layer- and subregion-specific differences in the neurophysiological properties of rat medial prefrontal cortex pyramidal neurons

Journal of Neurophysiology ◽

10.1152/jn.00146.2017 ◽

2018 ◽

Vol 119 (1) ◽

pp. 177-191 ◽

Cited By ~ 7

Author(s):

Chenghui Song ◽

James R. Moyer

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Pyramidal Neurons ◽

Conditioned Fear ◽

Input Resistance ◽

Underlying Mechanism ◽

Fear Memory ◽

Membrane Properties ◽

Spike Threshold ◽

Memory Acquisition

Medial prefrontal cortex (mPFC) is critical for the expression of long-term conditioned fear. However, the neural circuits involving fear memory acquisition and retrieval are still unclear. Two subregions within mPFC that have received a lot of attention are the prelimbic (PL) and infralimbic (IL) cortices (e.g., Santini E, Quirk GJ, Porter JT. J Neurosci 28: 4028–4036, 2008; Song C, Ehlers VL, Moyer JR Jr. J Neurosci 35: 13511–13524, 2015). Interestingly, PL and IL may play distinct roles during fear memory acquisition and retrieval but the underlying mechanism is poorly understood. One possibility is that the intrinsic membrane properties differ between these subregions. Thus, the current study was carried out to characterize the basic membrane properties of mPFC neurons in different layers and subregions. We found that pyramidal neurons in L2/3 were more hyperpolarized and less excitable than in L5. This was observed in both IL and PL and was associated with an enhanced h-current in L5 neurons. Within L2/3, IL neurons were more excitable than those in PL, which may be due to a lower spike threshold and higher input resistance in IL neurons. Within L5, the intrinsic excitability was comparable between neurons obtained in IL and PL. Thus, the heterogeneity in physiological properties of mPFC neurons may underlie the observed subregion-specific contribution of mPFC in cognitive function and emotional control, such as fear memory expression. NEW & NOTEWORTHY This is the first study to demonstrate that medial prefrontal cortical (mPFC) neurons are heterogeneous in both a layer- and a subregion-specific manner. Specifically, L5 neurons are more depolarized and more excitable than those neurons in L2/3, which is likely due to variations in h-current. Also, infralimbic neurons are more excitable than those of prelimbic neurons in layer 2/3, which may be due to differences in certain intrinsic properties, including input resistance and spike threshold.

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Reorganization of learning-associated prefrontal synaptic plasticity between the recall of recent and remote fear extinction memory

Learning & Memory ◽

10.1101/lm.625407 ◽

2007 ◽

Vol 14 (8) ◽

pp. 520-524 ◽

Cited By ~ 59

Author(s):

S. Hugues ◽

R. Garcia

Keyword(s):

Synaptic Plasticity ◽

Fear Extinction ◽

Extinction Memory

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Morphology of Pyramidal Neurons in the Rat Prefrontal Cortex: Lateralized Dendritic Remodeling by Chronic Stress

Neural Plasticity ◽

10.1155/2007/46276 ◽

2007 ◽

Vol 2007 ◽

pp. 1-14 ◽

Cited By ~ 46

Author(s):

Claudia Perez-Cruz ◽

Jeanine I. H. Müller-Keuker ◽

Urs Heilbronner ◽

Eberhard Fuchs ◽

Gabriele Flügge

Keyword(s):

Prefrontal Cortex ◽

Pyramidal Neurons ◽

Right Hemisphere ◽

Anterior Cingulate ◽

Chronic Restraint Stress ◽

Hemispheric Difference ◽

Infralimbic Cortex ◽

Dendritic Length ◽

The Right ◽

Apical Dendrites

The prefrontal cortex (PFC) plays an important role in the stress response. We filled pyramidal neurons in PFC layer III with neurobiotin and analyzed dendrites in rats submitted to chronic restraint stress and in controls. In the right prelimbic cortex (PL) of controls, apical and distal dendrites were longer than in the left PL. Stress reduced the total length of apical dendrites in right PL and abolished the hemispheric difference. In right infralimbic cortex (IL) of controls, proximal apical dendrites were longer than in left IL, and stress eliminated this hemispheric difference. No hemispheric difference was detected in anterior cingulate cortex (ACx) of controls, but stress reduced apical dendritic length in left ACx. These data demonstrate interhemispheric differences in the morphology of pyramidal neurons in PL and IL of control rats and selective effects of stress on the right hemisphere. In contrast, stress reduced dendritic length in the left ACx.

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Effects of Elevation of Brain Magnesium on Fear Conditioning, Fear Extinction, and Synaptic Plasticity in the Infralimbic Prefrontal Cortex and Lateral Amygdala

Journal of Neuroscience ◽

10.1523/jneurosci.3782-11.2011 ◽

2011 ◽

Vol 31 (42) ◽

pp. 14871-14881 ◽

Cited By ~ 57

Author(s):

N. Abumaria ◽

B. Yin ◽

L. Zhang ◽

X.-Y. Li ◽

T. Chen ◽

...

Keyword(s):

Prefrontal Cortex ◽

Synaptic Plasticity ◽

Fear Conditioning ◽

Fear Extinction ◽

Lateral Amygdala

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Enhanced synchronization between prelimbic and infralimbic cortices during fear extinction learning

Molecular Brain ◽

10.1186/s13041-021-00884-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Mayumi Watanabe ◽

Akira Uematsu ◽

Joshua P. Johansen

Keyword(s):

Prefrontal Cortex ◽

Neural Activity ◽

Fear Extinction ◽

Synaptic Connectivity ◽

Prelimbic Cortex ◽

Field Potentials ◽

Infralimbic Cortex ◽

Extinction Learning ◽

Gamma Frequency ◽

Learned Fear

AbstractThe ability to extinguish aversive memories when they are no longer associated with danger is critical for balancing survival with competing adaptive demands. Previous studies demonstrated that the infralimbic cortex (IL) is essential for extinction of learned fear, while neural activity in the prelimbic cortex (PL) facilitates fear responding and is negatively correlated with the strength of extinction memories. Though these adjacent regions in the prefrontal cortex maintain mutual synaptic connectivity, it has been unclear whether PL and IL interact functionally with each other during fear extinction learning. Here we addressed this question by recording local field potentials (LFPs) simultaneously from PL and IL of awake behaving rats during extinction of auditory fear memories. We found that LFP power in the fast gamma frequency (100–200 Hz) in both PL and IL regions increased during extinction learning. In addition, coherency analysis showed that synchronization between PL and IL in the fast gamma frequency was enhanced over the course of extinction. These findings support the hypothesis that interregional interactions between PL and IL increase as animals extinguish aversive memories.

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Faculty Opinions recommendation of Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727002762.793567212 ◽

2019 ◽

Author(s):

Amy Milton

Keyword(s):

Fear Extinction ◽

Female Rats ◽

Infralimbic Cortex ◽

Central Amygdala ◽

Extinction Memory

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The accumulation of N6-methyl-2’-deoxyadenosine in DNA drives activity-induced gene expression and is required for the extinction of conditioned fear

10.1101/059972 ◽

2016 ◽

Cited By ~ 1

Author(s):

Xiang Li ◽

Qiongyi Zhao ◽

Wei Wei ◽

Quan Lin ◽

Christophe Magnan ◽

...

Keyword(s):

Gene Expression ◽

Cortical Neurons ◽

Conditioned Fear ◽

Fear Extinction ◽

Adult Brain ◽

Extinction Learning ◽

Prefrontal Cortical ◽

Genome Wide ◽

Extinction Memory ◽

The Brain

Here we report that the recently discovered mammalian DNA modification N6-methyl-2’-deoxyadenosine (m6dA) is dynamically regulated in primary cortical neurons, and accumulates along promoters and coding sequences within the genome of activated prefrontal cortical neurons of adult C57/BI6 mice in response to fear extinction learning. The deposition of m6dA is generally associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with fear extinction learning-induced gene expression. Of particular relevance for fear extinction memory, the accumulation of m6dA is associated with an active chromatin state and the recruitment of transcriptional machinery to the brain-derived neurotrophic factor (Bdnf) P4 promoter, which is required for Bdnf exon IV mRNA expression and for the extinction of conditioned fear. These results expand the scope of DNA modifications in the adult brain and highlight changes in m6dA as a novel neuroepigenetic mechanism associated with activity-induced gene expression and the formation of fear extinction memory.

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