Retrieving fear memories, as time goes by…

Abstract

Research in fear conditioning has provided a comprehensive picture of the neuronal circuit underlying the formation of fear memories. In contrast, our understanding of the retrieval of fear memories is much more limited. This disparity may stem from the fact that fear memories are not rigid, but reorganize over time. To bring some clarity and raise awareness about the time-dependent dynamics of retrieval circuits, we review current evidence on the neuronal circuitry participating in fear memory retrieval at both early and late time points following auditory fear conditioning. We focus on the temporal recruitment of the paraventricular nucleus of the thalamus (PVT) for the retrieval and maintenance of fear memories. Finally, we speculate as to why retrieval circuits change with time, and consider the functional strategy of recruiting structures not previously considered as part of the retrieval circuit.

Fig. 1. Temporal reorganization of the circuits necessary for retrieval of auditory fear memories

Left - Retrieval of fear memories at early time points after conditioning recruits reciprocal activity between the amygdala and PL. During early retrieval, the conditioned tone activates auditory thalamus inputs to LA. Increased activity in LA neurons activates Som⁺ neurons in CeL, thereby disinhibiting CeM output neurons that mediate fear responses. Increased activity in LA neurons also activates BA neurons interconnected with PL, thereby allowing a top-down control of fear retrieval. Right - Retrieval of fear memories at late time points after conditioning recruits activity in PL neurons projecting to PVT, as well as PVT neurons projecting to CeL. During late retrieval, the conditioned tone activates auditory cortex inputs to both LA and PL. Increased activity in PL interneurons inhibits PV⁺ interneurons, thereby disinhibiting PL neurons projecting to PVT. Increased activity in PVT neurons activates Som⁺ neurons in CeL, and consequently disinhibits CeM output neurons that mediate fear responses. Legend: PL= prelimbic cortex, sup= superficial, PVT= paraventricular nucleus of the thalamus, LA= lateral amygdala, BA= basal amygdala, CeL= lateral portion of the central amygdala, CeM= medial portion of the central amygdala, cc= corpus callosum, 3V= third ventricle, PV⁺= parvalbumin positive neurons, Som⁺= somastotatin positive neurons, Som⁻= somatostatin negative neurons.

Fig. 2. Recruitment of PVT into the fear circuit may serve to integrate aversive memories with adaptive biological responses

The paraventricular nucleus of the thalamus (PVT) is reciprocally interconnected with the medial prefrontal cortex (mPFC), the hypothalamus (Hypo), and the central nucleus of the amygdala (CeA). In addition, PVT is the major source of inputs to the nucleus accumbens (NAcc). This pattern of anatomical connections places PVT in a central position to integrate aversive memories and anxiety (through connections with CeA) with adaptive biological responses such as arousal and defensive strategies (through connections with the mPFC), motivation and control of food intake (through projections to the NAcc), and regulation of circadian rhythms and stress responses (through connections with the hypothalamus).