The amygdala and the hippocampus are critically involved in the formation and retention of fear memories. However, their precise contribution to, and their interplay during, fear memory formation are not fully understood. In the present study we investigated network activities in the amygdalo-hippocampal system of freely behaving mice at different stages of fear memory consolidation and retention. Our data show enhanced theta phase synchronization in this pathway during the retrieval of fear memory at long-term (24 h post-training), but not short-term (2 min, 30 min and 2 h post-training) stages, following both contextual and auditory cued conditioning. However, retrieval of remotely conditioned fear (30 days post-training) failed to induce an increase in synchronization despite there still being memory retention. Thus, our data indicate that the amygdalo-hippocampal interaction reflects a dynamic interaction of ensemble activities related to various stages of fear memory consolidation and/or retention, and support the notion that recent and remote memories are organized through different network principles.
"As the needle was inserted into the brain, EEG and theta oscillation data were recorded and analyzed at each 0.05-0.1 mm of depth. For regular injection without EEG monitoring, the reported coordinates, AP: -1.94 mm, ML: 1.00 mm, DV: 1.25 mm, were employed in ten injections [22,23]. In addition, we calculated the presumable coordinates, AP: -2.18 mm, ML: ±1.6 mm, DV: 1.00 mm, based on the mouse brain atlas and performed twenty injections without EEG monitoring . "
[Show abstract][Hide abstract] ABSTRACT: Methods of cell biology and electrophysiology using dissociated primary cultured neurons allow in vitro study of molecular functions; however, analysis of intact neuronal circuitry is often preferable. To investigate exogenous genes, viral vectors are most commonly injected using a pipette that is inserted from the top of the cortex. Although there are few reports that describe the success rate of injection in detail, it is sometimes difficult to locate the pipette tip accurately within the CA1 pyramidal cell layer because the pyramidal layer is only 0.1 mm thick. In the present study, we have developed a system to inject viral vectors accurately into the mouse hippocampal CA1 pyramidal cell layer using a stereotaxic injection system with simultaneous electrophysiological monitoring of theta oscillation. The pipette tip was positioned reliably based on integrated values of the theta oscillation in the hippocampal CA1 pyramidal cell layer. This approach allows accurate injection of solutions and provides an efficient method of gene transfer using viral vectors into the hippocampus, which can be a useful tool for studies involving the molecular mechanisms of neuronal functions.
PLoS ONE 12/2013; 8(12):e83129. DOI:10.1371/journal.pone.0083129 · 3.23 Impact Factor
"Spikes of individual neurons were sorted by time-amplitude window discrimination and principal component analysis (OfflineSorter, Plexon Inc., Dallas, Texas USA), and verified through quantification of cluster separation (Figure 1B). Electrophysiological analyses (see below) were confined to the entire length of the first CS+ presentation (10 s) in R1, R6 and E. Additionally, as increases in theta coupling have previously been related to conditioned fear behavior , , , , electrophysiological analyses were further differentiated to data segments, during which the animals displayed freezing or no freezing while exposed the first presented conditioned stimulus (CS+) of R1, R6 and E. "
[Show abstract][Hide abstract] ABSTRACT: Theta oscillations are considered crucial mechanisms in neuronal communication across brain areas, required for consolidation and retrieval of fear memories. One form of inhibitory learning allowing adaptive control of fear memory is extinction, a deficit of which leads to maladaptive fear expression potentially leading to anxiety disorders. Behavioral responses after extinction training are thought to reflect a balance of recall from extinction memory and initial fear memory traces. Therefore, we hypothesized that the initial fear memory circuits impact behavioral fear after extinction, and more specifically, that the dynamics of theta synchrony in these pathways signal the individual fear response. Simultaneous multi-channel local field and unit recordings were obtained from the infralimbic prefrontal cortex, the hippocampal CA1 and the lateral amygdala in mice. Data revealed that the pattern of theta coherence and directionality within and across regions correlated with individual behavioral responses. Upon conditioned freezing, units were phase-locked to synchronized theta oscillations in these pathways, characterizing states of fear memory retrieval. When the conditioned stimulus evoked no fear during extinction recall, theta interactions were directional with prefrontal cortical spike firing leading hippocampal and amygdalar theta oscillations. These results indicate that the directional dynamics of theta-entrained activity across these areas guide changes in appraisal of threatening stimuli during fear memory and extinction retrieval. Given that exposure therapy involves procedures and pathways similar to those during extinction of conditioned fear, one therapeutical extension might be useful that imposes artificial theta activity to prefrontal cortical-amygdalo-hippocampal pathways that mimics the directionality signaling successful extinction recall.
PLoS ONE 10/2013; 8(10):e77707. DOI:10.1371/journal.pone.0077707 · 3.23 Impact Factor
"Specifically, 5-HTTOE mice exhibited reduced theta power evoked by fearful stimuli. Theta oscillations are consistently observed in the amygdala during fear conditioning (31–33) and can be intrinsically generated by amygdala neurons (32,34). However, it is debated whether amygdala theta, as observed at a population level in the LFP, is locally generated or volume conducted from neighboring regions such as the hippocampus (see Supplement 1 for further discussion). "
[Show abstract][Hide abstract] ABSTRACT: Gene association studies detect an influence of natural variation in the 5-hydroxytryptamine transporter (5-HTT) gene on multiple aspects of individuality in brain function, ranging from personality traits through to susceptibility to psychiatric disorders such as anxiety and depression. The neural substrates of these associations are unknown. Human neuroimaging studies suggest modulation of the amygdala by 5-HTT variation, but this hypothesis is controversial and unresolved, and difficult to investigate further in humans.
We used a mouse model in which the 5-HTT is overexpressed throughout the brain and recorded hemodynamic responses (using a novel in vivo voltammetric monitoring method, analogous to blood oxygen level-dependent functional magnetic resonance imaging) and local field potentials during Pavlovian fear conditioning.
Increased 5-HTT expression impaired, but did not prevent, fear learning and significantly reduced amygdala hemodynamic responses to aversive cues. Increased 5-HTT expression was also associated with reduced theta oscillations, which were a feature of aversive cue presentation in controls. Moreover, in control mice, but not those with high 5-HTT expression, there was a strong correlation between theta power and the amplitude of the hemodynamic response.
Direct experimental manipulation of 5-HTT expression levels throughout the brain markedly altered fear learning, amygdala hemodynamic responses, and neuronal oscillations.
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