Enhanced Extinction of Aversive Memories by High-Frequency Stimulation of the Rat Infralimbic Cortex

Electrical stimulation of the rodent medial prefrontal cortex (mPFC), including the infralimbic cortex (IL), immediately prior to or during fear extinction training facilitates extinction memory. Here we examined the effects of high-frequency stimulation (HFS) of the rat IL either prior to conditioning or following retrieval of the conditioned memory, on extinction of Pavlovian fear and conditioned taste aversion (CTA). IL-HFS applied immediately after fear memory retrieval, but not three hours after retrieval or prior to conditioning, subsequently reduced freezing during fear extinction. Similarly, IL-HFS given immediately, but not three hours after, retrieval of a CTA memory reduced aversion during extinction. These data indicate that HFS of the IL may be an effective method for reducing both learned fear and learned aversion

Decreased reproducibility and abnormal experience-dependent plasticity of network dynamics in Fragile X circuits.

Fragile X syndrome is a neurodevelopmental disorder associated with a broad range of neural phenotypes. Interpreting these findings has proven challenging because some phenotypes may reflect compensatory mechanisms or normal forms of plasticity differentially engaged by experiential differences. To help minimize compensatory and experiential influences, we used an ex vivo approach to study network dynamics and plasticity of cortical microcircuits. In Fmr1-/y circuits, the spatiotemporal structure of Up-states was less reproducible, suggesting alterations in the plasticity mechanisms governing network activity. Chronic optical stimulation revealed normal homeostatic plasticity of Up-states, however, Fmr1-/y circuits exhibited abnormal experience-dependent plasticity as they did not adapt to chronically presented temporal patterns in an interval-specific manner. These results, suggest that while homeostatic plasticity is normal, Fmr1-/y circuits exhibit deficits in the ability to orchestrate multiple forms of synaptic plasticity and to adapt to sensory patterns in an experience-dependent manner-which is likely to contribute to learning deficits

Decreased reproducibility and abnormal experience-dependent plasticity of network dynamics in Fragile X circuits.

Fragile X syndrome is a neurodevelopmental disorder associated with a broad range of neural phenotypes. Interpreting these findings has proven challenging because some phenotypes may reflect compensatory mechanisms or normal forms of plasticity differentially engaged by experiential differences. To help minimize compensatory and experiential influences, we used an ex vivo approach to study network dynamics and plasticity of cortical microcircuits. In Fmr1-/y circuits, the spatiotemporal structure of Up-states was less reproducible, suggesting alterations in the plasticity mechanisms governing network activity. Chronic optical stimulation revealed normal homeostatic plasticity of Up-states, however, Fmr1-/y circuits exhibited abnormal experience-dependent plasticity as they did not adapt to chronically presented temporal patterns in an interval-specific manner. These results, suggest that while homeostatic plasticity is normal, Fmr1-/y circuits exhibit deficits in the ability to orchestrate multiple forms of synaptic plasticity and to adapt to sensory patterns in an experience-dependent manner-which is likely to contribute to learning deficits

Short-Term Synaptic Plasticity as a Mechanism for Sensory Timing

The ability to detect time intervals and temporal patterns is critical to some of the most fundamental computations the brain performs, including the ability to communicate and appraise a dynamically changing environment. Many of these computations take place on the scale of tens to hundreds of milliseconds. Electrophysiological evidence shows that some neurons respond selectively to duration, interval, rate, or order. Because the time constants of many time-varying neural and synaptic properties, including short-term synaptic plasticity (STP), are also in the range of tens to hundreds of milliseconds, they are strong candidates to underlie the formation of temporally selective neurons. Neurophysiological studies indicate that STP is indeed one of the mechanisms that contributes to temporal selectivity, and computational models demonstrate that neurons embedded in local microcircuits exhibit temporal selectivity if their synapses undergo STP. Converging evidence suggests that some forms of temporal selectivity emerge from the dynamic changes in the balance of excitation and inhibition imposed by STP

Differential Excitability of PV and SST Neurons Results in Distinct Functional Roles in Inhibition Stabilization of Up States.

Up states are the best studied example of an emergent neural dynamic regime. Computational models based on a single class of inhibitory neurons indicate that Up states reflect bistable dynamic systems in which positive feedback is stabilized by strong inhibition and predict a paradoxical effect in which increased drive to inhibitory neurons results in decreased inhibitory activity. To date, however, computational models have not incorporated empirically defined properties of parvalbumin (PV) and somatostatin (SST) neurons. Here we first experimentally characterized the frequency-current (F-I) curves of pyramidal (Pyr), PV, and SST neurons from mice of either sex, and confirmed a sharp difference between the threshold and slopes of PV and SST neurons. The empirically defined F-I curves were incorporated into a three-population computational model that simulated the empirically derived firing rates of pyramidal, PV, and SST neurons. Simulations revealed that the intrinsic properties were sufficient to predict that PV neurons are primarily responsible for generating the nontrivial fixed points representing Up states. Simulations and analytical methods demonstrated that while the paradoxical effect is not obligatory in a model with two classes of inhibitory neurons, it is present in most regimes. Finally, experimental tests validated predictions of the model that the Pyr ↔ PV inhibitory loop is stronger than the Pyr ↔ SST loop.SIGNIFICANCE STATEMENT Many cortical computations, such as working memory, rely on the local recurrent excitatory connections that define cortical circuit motifs. Up states are among the best studied examples of neural dynamic regimes that rely on recurrent excitatory excitation. However, this positive feedback must be held in check by inhibition. To address the relative contribution of PV and SST neurons, we characterized the intrinsic input-output differences between these classes of inhibitory neurons and, using experimental and theoretical methods, show that the higher threshold and gain of PV leads to a dominant role in network stabilization

IL-HFS applied immediately before conditioning does not alter fear during extinction.

<p>(<b>A</b>) Schematic diagram showing electrode placement in IL <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035853#pone.0035853-Paxinos1" target="_blank">[56]</a> for the fear conditioning experiments. (<b>B</b>) Timeline of behavioral testing and stimulation. (<b>C</b>) Percent freezing to CS during conditioning, fear retrieval, and extinction in rats receiving either sham or HFS prior to conditioning. Sham and HFS rats did not differ during any phase. Data are Means ±SEM.</p

IL-HFS applied immediately after fear retrieval/short extinction training reduces fear during extinction.

<p>(<b>A</b>) Schematic diagram showing electrode placement in IL for the fear conditioning experiments. Diagram adapted from Paxinos and Watson 1998. (<b>B</b>) Timeline of behavioral testing and stimulation. (<b>C</b>) Percent freezing (mean ± SEM) to CS during conditioning, fear retrieval, and extinction in rats receiving either sham or HFS after fear retrieval. HFS rats showed reduced fear during extinction relative to Shams (**<i>P</i><.01). (<b>D</b>) Percent freezing to CS during reconditioning and extinction in rats receiving either sham or HFS after fear retrieval. Reconditioning and re-extinction were not affected by prior IL stimulation. Data are Means ±SEM.</p

IL-HFS applied immediately after CTA retrieval/short extinction does not affect the aversion index during extinction.

<p>(<b>A</b>) Schematic diagram showing electrode placement in IL for the CTA experiment. (<b>B</b>) Timeline of behavioral testing and stimulation. (<b>C</b>) Aversion index (mL water drunk/total fluid drunk×100) during conditioning, retrieval, and extinction in rats receiving either sham or HFS 3 hrs after retrieval. HFS rats were not different from Shams. Data are Means ±SEM.</p