Encoding of emotion-paired spatial stimuli in the rodent hippocampus

Abstract

Rats can acquire the cognitive component of CS-US associations between sensory and aversive stimuli without a functional basolateral amygdala (BLA). Thus, other brain regions should support such associations. Some septal/dorsal CA1 (dCA1) neurons respond to both spatial stimuli and footshock, suggesting that dCA1 could be one such region. We report that, in both dorsal and ventral hippocampus, different neuronal ensembles express immediate-early genes (IEGs) when a place is experienced alone vs. when it is associated with foot shock. We assessed changes in the size and overlap of hippocampal neuronal ensembles activated by two behavioral events using a cellular imaging method, Arc/Homer1a catFISH. The control group (A-A) experienced the same place twice, while the experimental group (A-CFC) received the same training plus two foot shocks during the second event. During fear conditioning, A-CFC, compared to A-A, rats had a smaller ensemble size in dCA3, dCA1, and vCA3, but not vCA1. Additionally, A-CFC rats had a lower overlap score in dCA1 and vCA3. Locomotion did not correlate with ensemble size. Importantly, foot shocks delivered in a training paradigm that prevents establishing shock-context associations, did not induce significant Arc expression, rejecting the possibility that the observed changes in ensemble size and composition simply reflect experiencing a foot shock. Combined with data that Arc is necessary for lasting synaptic plasticity and long-term memory, the data suggests that Arc/H1a+ hippocampal neuronal ensembles encode aspects of fear conditioning beyond space and time. Rats, like humans, may use the hippocampus to create integrated episodic-like memory during fear conditioning.

Altered hippocampal function before emotional trauma in rats susceptible to PTSD-like behaviors

“…Sus rats, compared to Res, showed a decreased overlap of activated ensembles in the dorsal/septal CA1 (dCA1) (Figure 3B), without a difference in the ensemble size (Figure 3A). Combined with previous findings that exploration of the same spatial environment leads to activation of largely overlapping neuronal ensembles as identified both electrophysiologically(Skaggs & McNaughton, 1998) and via the catFISH method (Guzowski et al, 1999; Nalloor et al, 2012; Ramírez-Amaya et al, 2005; Rosi et al, 2009; Vazdarjanova & Guzowski, 2004; Vazdarjanova et al, 2006; Vazdarjanova et al, 2002), the decreased overlap in dCA1 of Sus rats suggests that the fidelity of their hippocampal representations is impaired. The hippocampus in humans is well known to support episodic memory (Manns & Eichenbaum, 2006; Ranganath, 2010; Squire et al, 2004) and there is growing consensus that the rodent hippocampus also encodes the ‘what’, ‘where’ and ‘when’ components of experienced events (Babb & Crystal, 2006; Eichenbaum et al, 2012; Eichenbaum, 2013; Ferbinteanu et al, 2006; Morris, 2001; Nalloor et al, 2012).…”

“…Combined with previous findings that exploration of the same spatial environment leads to activation of largely overlapping neuronal ensembles as identified both electrophysiologically(Skaggs & McNaughton, 1998) and via the catFISH method (Guzowski et al, 1999; Nalloor et al, 2012; Ramírez-Amaya et al, 2005; Rosi et al, 2009; Vazdarjanova & Guzowski, 2004; Vazdarjanova et al, 2006; Vazdarjanova et al, 2002), the decreased overlap in dCA1 of Sus rats suggests that the fidelity of their hippocampal representations is impaired. The hippocampus in humans is well known to support episodic memory (Manns & Eichenbaum, 2006; Ranganath, 2010; Squire et al, 2004) and there is growing consensus that the rodent hippocampus also encodes the ‘what’, ‘where’ and ‘when’ components of experienced events (Babb & Crystal, 2006; Eichenbaum et al, 2012; Eichenbaum, 2013; Ferbinteanu et al, 2006; Morris, 2001; Nalloor et al, 2012). There is also increasing understanding that while both dCA1 and dCA3 encode the ‘what’ aspects of episodic-like memories, they also contribute differently: the dCA3 supporting spatial encoding, while the dCA1- temporal/sequential encoding (Eichenbaum, 2013; Hunsaker et al, 2008; Hunsaker & Kesner, 2008; Leutgeb, et al, 2004; Nalloor et al, 2012; Vazdarjanova & Guzowski, 2004).…”

“…The Arc/Homer1a catFISH (cellular compartmental analysis of temporal activity using fluorescence in situ hybridization) method (Vazdarjanova et al, 2002) is a sensitive technique that utilizes the expression of two plasticity-associated immediate-early genes, Arc and Homer1a ( H1a ), to identify and dissociate large neuronal ensembles activated during either of two events (Nalloor et al, 2012; Ramírez-Amaya et al, 2005; Rosi et al, 2009; Vazdarjanova & Guzowski, 2004; Vazdarjanova et al, 2006). For the purpose of brevity, we are using the term “activated” to describe neurons which have experienced plasticity-inducing events sufficient to initiate transcription of plasticity-related immediate-early genes.…”

“…For the purpose of brevity, we are using the term “activated” to describe neurons which have experienced plasticity-inducing events sufficient to initiate transcription of plasticity-related immediate-early genes. Rats pre-classified as susceptible or resistant to developing a PTSD-like phenotype (Nalloor et al, 2012) were allowed to explore a novel place twice (Experiment I) or explore the place once and then receive a footshock during a second exploration (Experiment II). Differences in functional activation of the septal/dorsal and temporal/ventral hippocampus (CA1 and CA3) between the two events were evaluated within the same rats using the Arc/H1a catFISH method and comparisons were made between susceptible and resistant rats.…”

Immediate-early gene transcriptional activation in hippocampus CA1 and CA3 does not accurately reflect rapid, pattern completion-based retrieval of context memory

“…IEG imaging has been used extensively to measure hippocampal network activity in response to exposure to an environmental context (Guzowski et al 1999(Guzowski et al , 2006Barot et al 2009;Miyashita et al 2009;Wiltgen et al 2010;Nalloor et al 2012;Nomura et al 2012;Pevzner et al 2012). However, despite the broad use of IEGs to visualize activated ensembles, the design of past behavioral studies has precluded specifying the transcriptional activation of IEGs explicitly to either the encoding or retrieval of a context memory.…”