Results Histology A total of 76 rats were tested. The photomicrograph in Figure 1A shows a representative electrode track in PL, and Figure 1B shows the placements of all stimulating electrodes. A total of 39 rats were stimulated in one of four mPFC subregions: PrCm, ACd, PL, or IL. To control for the effects of electrode implantation, 37 rats were implanted with stimulating electrodes in the corresponding regions, but were never stimulated (Unstim group). The n for individual experiments are given in the figure legends. | Figure 1.Placements of stimulating electrodes in different prefrontal subregions. (A) Photomicrograph showing the tip of a stimulating electrode in PL (arrow). (B) Coronal drawings (bregma +3.20 mm) showing the location of stimulating electrodes in PrCm, ACd, (more ...) |
Microstimulation of ACd and PrCm has no effect on fear expression or extinction On Day 1, rats were fear-conditioned and treatment groups were matched for final conditioning level. On Day 2, all rats were exposed to partial extinction training consisting of eight tones. In the stimulated group, extinction tones were paired with microstimulation of either PrCm, ACd, or PL. The latency of stimulation was 100–400 msec after tone onset, which corresponds to the latency of naturally occurring tone responses in these areas ( Peterson 1986; Yajeya et al. 1988; Baeg et al. 2001; Milad and Quirk 2002). As shown in Figure 2A,B, microstimulation of PrCm and ACd had no effect on the expression of freezing during extinction training. A repeated measures ANOVA performed on the extinction data showed no difference between stimulated and unstimulated groups for PrCm ( F(1,12) = 0.003; P = 0.96; see Fig. 2A) or ACd ( F(1,14) = 0.10; P = 0.75; see Fig. 2B). On Day 3, in the absence of microstimulation, there was also no difference between groups in either structure (PrCm: 67% freezing; Unstim: 60% freezing; t(18) = 0.73; P = 0.48; ACd: 44%; Unstim: 44%; t(14) = 0.009; P = 0.99). Recovery of freezing on Day 3 (a measure of extinction recall) also did not differ between groups in PrCm ( t(18) = 0.60; P = 0.55) and ACd ( t(14) = 0.40; P = 0.69). Thus, microstimulation of PrCm and ACd had no observable effects on expression or extinction of conditioned fear. | Figure 2.PL microstimulation, but not PrCm or ACd, impairs extinction. (A) Microstimulation of PrCm (n = 7) or (B) ACd (n = 7) on Day 2 had no effect on acquisition of extinction or subsequent retrieval of extinction (Day 3) when compared with Unstim group (n (more ...) |
Microstimulation of PL impairs extinction In contrast to PrCm and ACd, microstimulation of PL impaired extinction. As shown in Figure 2C, rats receiving PL microstimulation showed a slower rate of extinction. A repeated measures ANOVA of the extinction data showed a trend toward an effect of group ( F(1,18) = 3.08, P = 0.096). The following day, in the absence of stimulation, freezing in PL-stimulated rats (69%) was significantly higher than the Unstim group (40%; t(18) = 2.53, P = 0.02). In fact, PL-stimulated rats recovered 93% of their acquired freezing, compared with only 48% in the Unstim group ( t(18) = 3.04, P = 0.007; Fig. 2C), suggesting that PL microstimulation prevented extinction learning. To facilitate between-structure comparisons, IL-stimulation data from our previously published study ( Milad et al. 2004) are reproduced in Figure 2D. Repeated measures ANOVA of these data showed a significant effect of treatment ( F(1,19) = 13.28, P = 0.0017) and trial block ( F(1,19) = 41.47, P < 0.001). The following day, in the absence of stimulation, IL rats froze significantly less than the Unstim group (30% vs. 62%; t(19) = 2.52, P = 0.02). Recovery of freezing on Day 3 was 41% in IL-stimulated rats, compared with 79% in the Unstim group ( t(19) = 2.83, P = 0.01). Thus, in the previous study, IL stimulation decreased the expression of conditioned freezing and strengthened extinction learning ( Milad et al. 2004). Microstimulation of PL and IL has opposite effects on fear expression and extinction. The above experiments suggest that microstimulation of PL and IL has opposite effects on the expression of conditioned fear. However, due to ceiling levels of freezing at the start of extinction, it was not possible to determine whether PL microstimulation augmented fear expression, independent of any effect on extinction. To address this question, we repeated the IL and PL stimulation in a separate experiment using a lower footshock intensity (0.3 mA instead of 0.5 mA). Under these conditions, PL microstimulation significantly increased conditioned freezing from the start of the extinction phase (see Fig. 3A). In the first extinction trial, freezing levels were 82%, 14%, and 51% for PL-stimulated, IL-stimulated, and Unstim groups, respectively (see Fig. 3B, left). One-way ANOVA revealed a significant effect of group ( F(2,23) = 12.26; P < 0.001) and post hoc analyses confirmed that both PL-stimulated and IL-stimulated animals differed significantly from Unstim animals (Unstim vs. IL: P = 0.020; Unstim vs. PL: P = 0.036; IL vs. PL: P < 0.001), confirming that PL and IL stimulation had opposite effects on conditioned freezing. | Figure 3.Under low footshock conditions, PL microstimulation increases fear expression, whereas IL microstimulation decreases fear expression. (A) On Day 2, PL microstimulation (n = 8) increased conditioned freezing whereas IL microstimulation (n = 6) decreased (more ...) |
On Day 3, in the absence of microstimulation, PL, IL, and Unstim animals froze 47%, 19%, and 17%, respectively (see Fig. 3A). One-way ANOVA showed a trend toward an effect of group, which did not reach significance ( F(2,23) = 2.82, P = 0.080). In contrast to our previous studies ( Milad and Quirk 2002; Milad et al. 2004), we did not observe facilitation of the extinction memory in IL-stimulated animals. This is likely due to a floor effect in freezing under low footshock conditions. Microstimulation of PL and IL had no effect on freezing if administered in the absence of the tone ( Fig. 3B, left, F(2,22) = 0.71, P = 0.50), suggesting that microstimulation does not induce spontaneous freezing, but instead modulates freezing elicited by the tone. |
Discussion In this study, we paired microstimulation with conditioned tones to determine the impact of tone-evoked activity in mPFC subregions on fear expression and extinction. We observed that PL microstimulation increased conditioned freezing and impaired extinction. IL microstimulation had the opposite effect, decreasing conditioned freezing and, under standard footshock conditions ( Milad and Quirk 2002; Milad et al. 2004), facilitating extinction. In contrast, microstimulation of ACd and PrCm had no effect on either fear expression or extinction. These findings suggest that tone responses in different prefrontal subregions differentially affect fear behavior. | Figure 4.Model of prelimbic (PL) and infralimbic (IL) interactions with the amygdala. During PL microstimulation, feedforward excitation activates (plus sign) the basal amygdala (BA) which in turn activates the medial division of the central nucleus (CeM) to produce (more ...) |
IL, on the other hand, does not project to BA, but instead projects to GABAergic cells in the lateral subdivision of the central nucleus (CeL) and intercalated (ITC) cell masses of the amygdala ( Cassell and Wright 1986; Sesack et al. 1989; Hurley et al. 1991; McDonald et al. 1996; Freedman et al. 2000; Vertes 2004). These GABAergic cells have been shown to exert inhibitory control over CeM output neurons ( Royer et al. 1999). Thus, as previously suggested ( Royer and Paré 2002; Quirk et al. 2003; Milad et al. 2004; Paré et al. 2004), IL may inhibit fear via the CeL/ITC cell groups. In support of this, electrical stimulation of IL inhibits the responsiveness of Ce neurons to BA stimulation ( Quirk et al. 2003) and chemical stimulation of IL increased c-Fos labeling in amygdala ITC cells ( Berretta et al. 2005). Thus, the differential projections of PL and IL to the amygdala may allow these structures to increase and decrease, respectively, the expression of conditioned fear. Moreover, the high frequency stimulation we used likely potentiated local circuitry within the mPFC ( Herry and Garcia 2002), mPFC targets in BA, or mPFC targets in ITC ( Royer and Paré 2002). Plasticity in these sites could explain the enduring effects of microstimulation that we observed. Recent studies support the idea that PL and IL have opposite effects on fear expression and extinction. Lesions restricted to IL impair recall of extinction ( Quirk et al. 2000; Lebron et al. 2004), causing increased freezing at test. Similarly, infusing antagonists of NMDA receptors ( Burgos-Robles et al. 2004), MAP kinase inhibitors ( Hugues et al. 2004, 2006), or protein synthesis inhibitors ( Santini et al. 2004) into IL impairs subsequent recall of extinction. These findings suggest that potentiation of IL inputs during extinction is necessary for suppressing fear during recall of extinction. Consistent with this, IL neurons do not signal conditioning, but signal extinction recall ( Milad and Quirk 2002; Barrett et al. 2003). Recent lesion studies, however, have reported that mPFC lesions have no effect on fear extinction ( Farinelli et al. 2006; Garcia et al. 2006). Lesions in those studies damaged both IL and PL and, in light of the opposite effects on freezing reported here, might be expected to have no net effect. In contrast to IL, PL lesions ( Joel et al. 1997) and mPFC inactivation (including PL) reduce the expression of conditioned fear ( Akirav et al. 2006; Blum et al. 2006; Sierra-Mercado et al. 2006). Finally, in support of opposite roles of IL and PL in fear expression, Gilmartin and McEchron (2005) recently observed that IL and PL neurons respond in an opposite manner to conditioned tones. Recently, there has been a surge of interest in the neurobiology of fear conditioning and extinction in humans, reflecting prevailing theories that these processes may be critical to the pathophysiology of anxiety disorders as well as their treatment by extinction-based behavioral therapies ( Milad et al. 2006; Rauch et al. 2006). Pertinent to our present findings, deep brain stimulation and transcranial magnetic stimulation have shown promise as treatments for mood and anxiety disorders ( George and Belmaker 2000; Greenberg and Rezai 2003; Nuttin et al. 2003). The advancement of neurostimulation therapies requires a sophisticated understanding of the mediating neuroanatomy. Neuroimaging studies have already begun to establish the human homologs of IL in the ventromedial prefrontal loci, which show structural and functional correlations with extinction recall ( Phelps et al. 2004; Milad et al. 2005). Our findings suggest that identifying a human homolog of PL, responsible for impeding extinction processes, might be of comparable importance. Inhibiting the function of the PL homolog via neurostimulation methods in humans could represent a viable means of facilitating extinction, as a treatment for anxiety disorders. In summary, we have demonstrated that there are separate modules within the mPFC that differentially affect fear expression in rats. Microstimulation findings suggest that tone-induced activity in PL increases fear expression and impairs extinction, while tone-induced activity in IL has the opposite effect. This suggests that mPFC is not functionally monolithic, but contains discrete subregions that differentially regulate fear behavior. Identification of homologous prefrontal subregions in rats and humans, and their respective roles in fear conditioning and extinction, will be needed to adequately translate rodent findings in order to advance human therapeutics. |
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