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A temporal shift in the circuits mediating retrieval of fear memory.

Do-Monte FH, Quiñones-Laracuente K, Quirk GJ - Nature (2015)

Bottom Line: In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits.Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear.Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Psychiatry, University of Puerto Rico School of Medicine, PO Box 365067, San Juan 00936, Puerto Rico [2] Department of Anatomy &Neurobiology, University of Puerto Rico School of Medicine, P.O. Box 365067, San Juan 00936, Puerto Rico.

ABSTRACT
Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning, but little is known about how retrieval circuits change with time. Here we show that the dorsal midline thalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28 days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, the paraventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showed increased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time after training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval, sends dense projections to the PVT. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.

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Conditioning levels in muscimol and optogenetic experimentsIn the muscimol experiments, levels of freezing to tones (pre-treatment) for the habituation phase (first two blocks) and conditioning phase (last three blocks) were similar for saline (SAL, white circles) and muscimol (MUS, green circles) groups at 0.5 h (a), 6 h (b), 24 h (c), 7 d (d) and 28 d (e). In the optogenetic experiments, freezing levels were similar for the eNpHR-eYFP groups (red circles) and the control groups (white circles) prior to manipulation of the following regions or pathways: PL-somata (f), PL-PVT projections (g), PL-BLA projections (h), PVT-CeA projections (i), BLA somata (j) and PVT-CeA projections during ITI (k). Data are shown as mean ± SEM in blocks of two trials.
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Figure 5: Conditioning levels in muscimol and optogenetic experimentsIn the muscimol experiments, levels of freezing to tones (pre-treatment) for the habituation phase (first two blocks) and conditioning phase (last three blocks) were similar for saline (SAL, white circles) and muscimol (MUS, green circles) groups at 0.5 h (a), 6 h (b), 24 h (c), 7 d (d) and 28 d (e). In the optogenetic experiments, freezing levels were similar for the eNpHR-eYFP groups (red circles) and the control groups (white circles) prior to manipulation of the following regions or pathways: PL-somata (f), PL-PVT projections (g), PL-BLA projections (h), PVT-CeA projections (i), BLA somata (j) and PVT-CeA projections during ITI (k). Data are shown as mean ± SEM in blocks of two trials.

Mentions: We found that inactivating dMT with GABA-A receptor agonist muscimol shortly after conditioning (0.5 h or 6 h) had no effect on fear retrieval, but inactivating dMT at later timepoints (24 h, 7 d and 28 d) impaired retrieval (Fig. 1a–c; conditioning levels shown in Extended Data Fig. 1a–e). The following day, in the absence of drug, retrieval remained impaired in the 7 d and 28 d groups (Fig. 1d), suggesting that dMT activity may be necessary for the maintenance of fear memory. In support of this, retrieval was still impaired one week following the initial retrieval test (day 14, see Extended Data Fig. 2a). Inactivation of dMT without retrieval had no effect (Extended Data Fig. 2b), suggesting a possible role of dMT in memory reconsolidation. Although intra-dMT infusion of drugs that block reconsolidation had no effect (Extended Data Fig. 2c,d), dMT activity could be facilitating memory reconsolidation in downstream structures (e.g. amygdala). Thus, with the passage of time, dMT activity becomes increasingly necessary first for retrieval and later for maintenance of fear memories.


A temporal shift in the circuits mediating retrieval of fear memory.

Do-Monte FH, Quiñones-Laracuente K, Quirk GJ - Nature (2015)

Conditioning levels in muscimol and optogenetic experimentsIn the muscimol experiments, levels of freezing to tones (pre-treatment) for the habituation phase (first two blocks) and conditioning phase (last three blocks) were similar for saline (SAL, white circles) and muscimol (MUS, green circles) groups at 0.5 h (a), 6 h (b), 24 h (c), 7 d (d) and 28 d (e). In the optogenetic experiments, freezing levels were similar for the eNpHR-eYFP groups (red circles) and the control groups (white circles) prior to manipulation of the following regions or pathways: PL-somata (f), PL-PVT projections (g), PL-BLA projections (h), PVT-CeA projections (i), BLA somata (j) and PVT-CeA projections during ITI (k). Data are shown as mean ± SEM in blocks of two trials.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4376623&req=5

Figure 5: Conditioning levels in muscimol and optogenetic experimentsIn the muscimol experiments, levels of freezing to tones (pre-treatment) for the habituation phase (first two blocks) and conditioning phase (last three blocks) were similar for saline (SAL, white circles) and muscimol (MUS, green circles) groups at 0.5 h (a), 6 h (b), 24 h (c), 7 d (d) and 28 d (e). In the optogenetic experiments, freezing levels were similar for the eNpHR-eYFP groups (red circles) and the control groups (white circles) prior to manipulation of the following regions or pathways: PL-somata (f), PL-PVT projections (g), PL-BLA projections (h), PVT-CeA projections (i), BLA somata (j) and PVT-CeA projections during ITI (k). Data are shown as mean ± SEM in blocks of two trials.
Mentions: We found that inactivating dMT with GABA-A receptor agonist muscimol shortly after conditioning (0.5 h or 6 h) had no effect on fear retrieval, but inactivating dMT at later timepoints (24 h, 7 d and 28 d) impaired retrieval (Fig. 1a–c; conditioning levels shown in Extended Data Fig. 1a–e). The following day, in the absence of drug, retrieval remained impaired in the 7 d and 28 d groups (Fig. 1d), suggesting that dMT activity may be necessary for the maintenance of fear memory. In support of this, retrieval was still impaired one week following the initial retrieval test (day 14, see Extended Data Fig. 2a). Inactivation of dMT without retrieval had no effect (Extended Data Fig. 2b), suggesting a possible role of dMT in memory reconsolidation. Although intra-dMT infusion of drugs that block reconsolidation had no effect (Extended Data Fig. 2c,d), dMT activity could be facilitating memory reconsolidation in downstream structures (e.g. amygdala). Thus, with the passage of time, dMT activity becomes increasingly necessary first for retrieval and later for maintenance of fear memories.

Bottom Line: In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits.Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear.Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Psychiatry, University of Puerto Rico School of Medicine, PO Box 365067, San Juan 00936, Puerto Rico [2] Department of Anatomy &Neurobiology, University of Puerto Rico School of Medicine, P.O. Box 365067, San Juan 00936, Puerto Rico.

ABSTRACT
Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning, but little is known about how retrieval circuits change with time. Here we show that the dorsal midline thalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28 days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, the paraventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showed increased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time after training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval, sends dense projections to the PVT. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.

Show MeSH
Related in: MedlinePlus