[Paper Review] Control over stress induces plasticity of individual prefrontal cortical neurons: A conductance-based neural simulation

Cooper, Don, Juan A. Varela+2 more|arXiv (Cornell University)|Jan 1, 2012

Neural dynamics and brain function1 citations

TL;DR

This study uses conductance-based neural simulations in NEURON to show that control over stress enhances prefrontal cortical (PFC) neuron excitability via increased Na+ and Ca2+ T-type voltage-gated conductances and leak conductance. The plasticity amplifies synaptic integration and action potential output, offering a biophysical mechanism for stress resilience and generating testable hypotheses for future electrophysiological research.

ABSTRACT

Behavioral control over stressful stimuli induces resilience to future conditions when control is lacking. The medial prefrontal cortex(mPFC) is a critically important brain region required for plasticity of stress resilience. We found that control over stress induces plasticity of the intrinsic voltage-gated conductances of pyramidal neurons in the PFC. To gain insight into the underlying biophysical mechanisms of this plasticity we used the conductance- based neural simulation software tool, NEURON, to model the increase in membrane excitability associated with resilience to stress. A ball and stick multicompartment conductance-based model was used to realistically fit passive and active data traces from prototypical pyramidal neurons in neurons in rats with control over tail shock stress and those lacking control. The results indicate that the plasticity of membrane excitability associated with control over stress can be attributed to an increase in Na+ and Ca2+ T-type conductances and an increase in the leak conductance. Using simulated dendritic synaptic inputs we observed an increase in excitatory postsynaptic summation and amplification resulting in elevated action potential output. This realistic simulation suggests that control over stress enhances the output of the PFC and offers specific testable hypotheses to guide future electrophysiological mechanistic studies in animal models of resilience and vulnerability to stress.

Motivation & Objective

• To understand the biophysical mechanisms underlying stress resilience induced by behavioral control over stress.
• To investigate how intrinsic membrane properties of prefrontal cortical (PFC) pyramidal neurons change in response to controllable vs. uncontrollable stress.
• To model the resulting increase in neuronal excitability and action potential output using a realistic multicompartment conductance-based approach.
• To generate testable hypotheses about ion channel plasticity that underlie stress resilience in PFC neurons.

Proposed method

• A ball-and-stick multicompartment conductance-based model was constructed to simulate rat prefrontal pyramidal neurons.
• Model parameters were fitted to experimental passive and active membrane data from rats with and without control over tail shock stress.
• Voltage-gated Na+ and Ca2+ T-type conductances, along with leak conductance, were systematically increased to simulate plasticity induced by stress control.
• Synaptic inputs were simulated at dendritic compartments to assess changes in excitatory postsynaptic potential summation and action potential output.
• The simulation compared neuronal responses between control and uncontrollable stress conditions to isolate conductance contributions to excitability.

Experimental results

Research questions

• RQ1 How does behavioral control over stress alter intrinsic membrane conductances in prefrontal cortical pyramidal neurons?
• RQ2 Which specific voltage-gated ion conductances contribute to increased neuronal excitability during stress resilience?
• RQ3 How does the plasticity of these conductances enhance synaptic integration and action potential output in PFC neurons?
• RQ4 What biophysical mechanisms underlie the increased output of the PFC associated with stress control?

Key findings

• An increase in Na+ and Ca2+ T-type voltage-gated conductances was identified as a key contributor to enhanced membrane excitability in PFC pyramidal neurons under stress control.
• Elevated leak conductance also contributed to the observed increase in neuronal excitability in the model.
• The simulation showed amplified excitatory postsynaptic potential summation due to changes in membrane conductance properties.
• Action potential output was significantly increased in response to synaptic inputs following simulated plasticity, indicating enhanced PFC output.
• The model successfully reproduced experimental data traces from both control and uncontrollable stress conditions, validating its biological realism.
• The findings suggest that conductance plasticity in PFC neurons provides a biophysical basis for stress resilience and offers specific, testable predictions for future electrophysiological studies.