Prefrontal single-unit firing associated with deficient extinction in mice

Abstract

The neural circuitry mediating fear extinction has been increasingly well studied and delineated. The rodent infralimbic subregion (IL) of the ventromedial prefrontal cortex (vmPFC) has been found to promote extinction, whereas the prelimbic cortex (PL) demonstrates an opposing, pro-fear, function. Studies employing in vivo electrophysiological recordings have observed that while increased IL single-unit firing and bursting predicts robust extinction retrieval, increased PL firing can correlate with sustained fear and poor extinction. These relationships between single-unit firing and extinction do not hold under all experimental conditions, however. In the current study, we further investigated the relationship between vmPFC and PL single-unit firing and extinction using inbred mouse models of intact (C57BL/6J, B6) and deficient (129S1/SvImJ, S1) extinction strains. Simultaneous single-unit recordings were made in the PL and vmPFC (encompassing IL) as B6 and S1 mice performed extinction training and retrieval. Impaired extinction retrieval in S1 mice was associated with elevated PL single-unit firing, as compared to firing in extinguishing B6 mice, consistent with the hypothesized pro-fear contribution of PL. Analysis of local field potentials also revealed significantly higher gamma power in the PL of Sthan B6 mice during extinction training and retrieval. In the vmPFC, impaired extinction in S1 mice was also associated with exaggerated single-unit firing, relative to B6 mice. This is in apparent contradiction to evidence that IL activity promotes extinction, but could reflect a (failed) compensatory effort by the vmPFC to mitigate fear-promoting activity in other regions, such as the PL or amygdala. In support of this hypothesis, augmenting IL activity via direct infusion of the GABAA receptor antagonist picrotoxin rescued impaired extinction retrieval in S1 mice. Chronic fluoxetine treatment produced modest reductions in fear during extinction retrieval and increased the number of Zif268-labeled cells in layer II of IL, but failed to increase vmPFC single-unit firing. Collectively, these findings further support the important contribution these cortical regions play in determining the balance between robust extinction on the one hand, and sustained fear on the other. Elucidating the precise nature of these roles could help inform understanding of the pathophysiology of fear-related anxiety disorders.

Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress

“…Neurons in both IL and PL exhibited much more dramatic changes in spontaneous firing immediately after CS-US pairings on day 1 than after presentation of the CS alone on day 2, despite similar (and nearly asymptotic) levels of freezing behavior in each session, particularly in vehicle-treated rats. These results indicate that it is not high levels of fear per se that correlate with changes in mPFC neuronal firing (23,24,(32)(33)(34), but rather the emotional context in which that fear is experienced (46,47). Specifically, our results suggest that mPFC firing is particularly sensitive to the acute effects of the footshock US, possibly reflecting unconditioned components of fear in the immediate aftermath of shock exposure.…”

“…It has previously been suggested that stress-induced changes in prefrontal cortical structure and function observed in animal models may contribute to the extinction deficits observed in patients with PTSD (22)(23)(24). Given the abundant literature implicating NE signaling in prefrontal cortical function (25,26), it is conceivable that stress-induced elevations in prefrontal NE release (27)(28)(29) contribute to extinction impairments associated with PTSD.…”

Effects of chronic ethanol exposure on neuronal function in the prefrontal cortex and extended amygdala

“…The robust effects of CIE on ILC neurons as compared to PLC neurons in mice may be related to their differing connectivity and roles in several behaviors mediated by the PFC (Fitzgerald et al, 2014; Holmes et al, 2012). For example, while PLC activation promotes fear behavior, ILC neuronal activity promotes extinction (Fitzgerald et al, 2014).…”

“…For example, while PLC activation promotes fear behavior, ILC neuronal activity promotes extinction (Fitzgerald et al, 2014). We have previously shown that CIE impairs fear extinction mediated by a reduction in NMDA receptor-dependent burst firing of ILC, but not PLC, neurons (Holmes et al, 2012), and we have also observed a decrease in expression of the neuroactive steroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP), a positive allosteric modulator of GABA A receptors, in the PFC (Maldonado-Devincci et al, 2014).…”

Amygdala Microcircuits Controlling Learned Fear

“…In contrast, most BA neurons show sustained responses that last for the entire CS duration and in some cases beyond, mirroring the persistence of conditioned fear responses (Amano et al, 2011). Interestingly, prelimbic (PL) neurons show a similar response pattern (Burgos-Robles et al, 2009; Fitzgerald et al, 2013; Courtin et al, 2014). Moreover, PL inactivation impairs fear expression (Corcoran and Quirk, 2007), and BLA inactivation abolishes tone responses in PL (Sotres-Bayon et al, 2012).…”