Dopamine D1-like receptors modulate synchronized oscillations in the hippocampal-prefrontal-amygdala circuit in contextual fear

Abstract

Contextual fear conditioning (CFC) is mediated by a neural circuit that includes the hippocampus, prefrontal cortex, and amygdala, but the neurophysiological mechanisms underlying the regulation of CFC by neuromodulators remain unclear. Dopamine D1-like receptors (D1Rs) in this circuit regulate CFC and local synaptic plasticity, which is facilitated by synchronized oscillations between these areas. In rats, we determined the effects of systemic D1R blockade on CFC and oscillatory synchrony between dorsal hippocampus (DH), prelimbic (PL) cortex, basolateral amygdala (BLA), and ventral hippocampus (VH), which sends hippocampal projections to PL and BLA. D1R blockade altered DH-VH and reduced VH-PL and VH-BLA synchrony during CFC, as inferred from theta and gamma coherence and theta-gamma coupling. D1R blockade also impaired CFC, as indicated by decreased freezing at retrieval, which was characterized by altered DH-VH and reduced VH-PL, VH-BLA, and PL-BLA synchrony. This reduction in VH-PL-BLA synchrony was not fully accounted for by non-specific locomotor effects, as revealed by comparing between epochs of movement and freezing in the controls. These results suggest that D1Rs regulate CFC by modulating synchronized oscillations within the hippocampus-prefrontal-amygdala circuit. They also add to growing evidence indicating that this circuit synchrony at retrieval reflects a neural signature of learned fear.

Figure 1

D1R blockade impairs CFC. (A) Schematic representation of the behavioral testing paradigm used. Rats received a systemic injection of SCH23390 (SCH) or vehicle (VEH) 30 min before conditioning, and LFPs were recorded during conditioning and retrieval testing. (B) SCH given before CFC decreased freezing at retrieval, compared to VEH (*P < 0.05). (C) A time course analysis showed that SCH resulted in decreased freezing throughout retrieval, compared to VEH (*P < 0.05). (D) Illustrative examples of electrode placements in (left; white arrows) and LFP signals recorded from (right) DH, VH, PL, and BLA. (E) Schematic representations of theta (8 Hz), low gamma (40 Hz), and high gamma (70 Hz) oscillations, and theta-gamma PAC at the low and high gamma frequencies.

Figure 2

D1R blockade alters DH–VH and reduces VH–PL and VH–BLA synchrony before CFC. (A) Acute effects of SCH23390 (SCH) on theta power before CFC. Peak theta power occurred ~ 7–8 Hz in controls treated with vehicle (VEH). Compared to VEH, SCH decreased peak theta power and increased power outside the peak in DH and VH (*P < 0.001), but not PL or BLA. (B) Acute effects of SCH on theta coherence before CFC. Peak theta coherence occurred ~ 7–9 Hz with VEH. Compared to VEH, SCH decreased DH–VH peak theta coherence and increased DH–VH coherence outside the peak (*P < 0.001). SCH decreased VH–PL and VH–BLA theta coherence, compared to VEH (*P < 0.001), without affecting PL–BLA theta coherence. (C) Acute effects of SCH on gamma power before CFC. SCH had no effect on gamma power in DH. Compared to VEH, SCH increased gamma power in VH and PL (*P < 0.001). SCH decreased high gamma power in BLA, compared to VEH (*P < 0.001). (D) Acute effects of SCH on gamma coherence before CFC. SCH increased DH-VH and decreased VH–PL gamma coherence, compared to VEH (*P < 0.001). SCH decreased VH–BLA low gamma coherence, compared to VEH (*P < 0.001), without affecting PL–BLA gamma coherence.

Figure 3

D1R blockade enhances theta-gamma coupling between DH and VH before CFC. (A) Theta-gamma PAC in each area after vehicle (VEH) treatment, with blue and red indicating lower and higher gamma amplitude, respectively. Peak PAC occurred at a theta frequency ~ 5 Hz in each area. (B) SCH23390 (SCH) had no effects on theta-gamma PAC in DH, VH, PL or BLA. (C) Theta-gamma PAC between areas with VEH, showing that peak PAC occurred ~ 5 Hz. (D) SCH increased DH theta coupling of VH gamma, compared to VEH (*P < 0.05). SCH had no effects on VH theta-PL gamma, VH theta-BLA gamma, or PL theta-BLA gamma PAC.

Figure 4

Impaired CFC by D1R blockade is associated with altered DH-VH and reduced VH–PL–BLA synchrony at retrieval. (A) Effects of SCH23390 (SCH) given before CFC on theta power at retrieval. Peak theta power occurred ~ 6–7 Hz in controls treated with vehicle (VEH), while SCH shifted the peak to ~ 7–8 Hz. In DH, SCH decreased lower and increased peak theta power, compared to VEH (*P < 0.001). In VH, SCH decreased lower and increased higher theta power, compared to VEH (*P < 0.001). In PL and BLA, SCH increased theta power, compared to VEH (*P < 0.001). (B) Effects of SCH given before CFC on theta coherence at retrieval. SCH increased DH–VH and decreased VH–PL, VH–BLA, and PL–BLA theta coherence, compared to VEH (*P < 0.001). (C) Effects of SCH given before CFC on gamma power at retrieval. A peak in low gamma power occurred ~ 35–40 Hz in DH, VH, and BLA, but not PL, with VEH. In DH, SCH decreased low and increased high gamma power, compared to VEH (*P < 0.001). In VH, SCH decreased peak low gamma power and increased low gamma power outside the peak, while increasing or decreasing power at various high gamma frequencies, compared to VEH (*P < 0.001). In PL and BLA, SCH decreased gamma power, compared to VEH (*P < 0.001). (D) Effects of SCH given before CFC on gamma coherence at retrieval. Peak low gamma coherence between DH and VH occurred at 35–40 Hz with VEH, but no peaks were observed for coherence between the other areas. SCH decreased DH–VH peak low gamma coherence and increased low gamma coherence outside the peak, while increasing or decreasing coherence at various high gamma frequencies, compared to VEH (*P < 0.001). SCH decreased VH–PL, VH–BLA, and PL–BLA gamma coherence, compared to VEH (*P < 0.001).

Figure 5

Impaired CFC by D1R blockade is associated with enhanced theta-gamma coupling between DH and VH at retrieval. (A) Theta-gamma PAC in each area after prior vehicle (VEH) treatment, with lower and higher gamma amplitude indicated by blue and red, respectively. Peak PAC occurred ~ 5 Hz in each area. (B) SCH23390 (SCH) given before CFC had no effects on theta-gamma PAC in DH, VH, PL or BLA. (C) Theta-gamma PAC between areas with prior VEH treatment, showing that peak PAC occurred ~ 5 Hz. (D) SCH given before CFC increased DH theta phase coupling of gamma amplitude in VH, compared to VEH (*P < 0.05). SCH given before CFC had no effects on VH theta-PL gamma, VH theta-BLA gamma, or PL theta-BLA gamma PAC.

Figure 6

Movement and freezing in vehicle-treated controls are associated with differences in DH–VH and VH–PL–BLA synchrony at retrieval. (A) Differences between movement (MOV) and freezing (FRE) in theta power at retrieval. Peak theta power occurred ~ 7–8 Hz with MOV. Compared to FRE, MOV increased peak theta power and decreased theta power outside the peak in DH and VH (*P < 0.001). In PL and BLA, MOV increased theta power, compared to FRE (*P < 0.001). (B) Differences between MOV and FRE in theta coherence at retrieval. Compared to FRE, MOV increased DH–VH, VH–BLA, and PL–BLA theta coherence (*P < 0.001). MOV decreased VH–PL theta coherence, compared to FRE (*P < 0.001). (C) Differences between MOV and FRE in gamma power at retrieval. A peak in low gamma power occurred ~ 35–40 Hz with FRE in DH and VH, but not PL or BLA. In DH, MOV decreased low and increased high gamma power, compared to FRE (*P < 0.001). In VH, MOV decreased low gamma power, while power was increased or decreased at various high gamma frequencies, compared to FRE (*P < 0.001). In PL, MOV increased high gamma power, compared to FRE (*P < 0.001). In BLA, MOV increased gamma power, compared to FRE (*P < 0.001). (D) Differences between MOV and FRE in gamma coherence at retrieval. Peak low gamma coherence between DH and VH occurred ~ 35–40 Hz with FRE, but there were no peaks for gamma coherence between other areas. MOV decreased DH-VH low gamma coherence, compared to FRE (*P < 0.001). MOV decreased VH–PL high gamma coherence, compared to FRE (*P < 0.001). MOV had no effects on VH–BLA or PL–BLA gamma coherence.

Figure 7

Movement in vehicle-treated controls enhances theta-gamma coupling in BLA at retrieval. (A) Theta-gamma PAC in each area during freezing (FRE), with lower and higher gamma amplitude indicated by blue and red, respectively. Peak PAC occurred ~ 5 Hz in each area. (B) Movement (MOV) had no effect on theta-gamma PAC in DH, VH, or PL. MOV increased theta coupling of low gamma in BLA, compared to FRE (*P < 0.05). (C) Theta-gamma PAC between areas during FRE, showing that peak PAC occurred ~ 5 Hz. (D) MOV had no effects on DH theta–VH gamma, VH theta–PL gamma, VH theta–BLA gamma, or PL theta–BLA gamma PAC.

Figure 8

Summary of the key effects of D1R blockade before CFC on hippocampal–prefrontal–amygdala synchrony before conditioning and at retrieval tested drug-free. (A) Dopamine projections from the ventral tegmental area (VTA) to DH, PL, and BLA (green lines) regulate CFC and local synaptic plasticity via D1R signalling. DH projects to PL and BLA indirectly through VH (black lines). (B) SCH23390 acts acutely before conditioning to alter intra-hippocampal (solid red line; decreased peak theta coherence, increased gamma coherence and theta-gamma PAC) and reduce hippocampal-prefrontal and hippocampal–amygdala (dashed red lines; decreased theta and gamma coherence) synchrony. (C) Impaired CFC by SCH23390 is associated with altered intra-hippocampal (solid red line; decreased gamma coherence, increased theta coherence and theta-gamma PAC) and reduced hippocampal–prefrontal–amygdala (dashed red lines; decreased theta and gamma coherence) synchrony at retrieval.