Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory

Abstract

Remodeling of cortical connectivity is thought to allow initially hippocampus-dependent memories to be expressed independently of the hippocampus at remote time points. Consistent with this, consolidation of a contextual fear memory is associated with dendritic spine growth in neurons of the anterior cingulate cortex (aCC). To directly test whether such cortical structural remodeling is necessary for memory consolidation, we disrupted spine growth in the aCC at different times following contextual fear conditioning in mice. We took advantage of previous studies showing that the transcription factor myocyte enhancer factor 2 (MEF2) negatively regulates spinogenesis both in vitro and in vivo. We found that increasing MEF2-dependent transcription in the aCC during a critical posttraining window (but not at later time points) blocked both the consolidation-associated dendritic spine growth and subsequent memory expression. Together, these data strengthen the causal link between cortical structural remodeling and memory consolidation and, further, identify MEF2 as a key regulator of these processes.structural plasticity | remote memory | viral vector I n experimental animals, damage to the hippocampus disproportionately impacts recently acquired memories, with relative sparing of remote memories (1-8). Such observations have led to the idea that the hippocampus is transiently required for memory expression, with remote memory expression being exclusively dependent on the cortex (9). According to one model (10), posttraining hippocampal activity coordinates reactivation of memory traces in the cortex. This reactivation leads to the remodeling of cortical connections, allowing the memory to eventually be expressed independently of the hippocampus. A recent study in mice (5) provided correlative evidence for posttraining remodeling of neurons in the anterior cingulate cortex (aCC), a subregion of the prefrontal cortex that plays an essential role in remote memory expression (11). Increases in dendritic spine density on layer 2/3 pyramidal aCC neurons were observed 1 mo, but not 1 d, following contextual fear conditioning (5). As layer 2/3 pyramidal neurons send and receive long-range cortical connections (12), such changes may contribute to increased functional connectivity between the aCC and other cortical areas important for remote memory expression (13,14). However, whether this increase in aCC spine density is necessary for memory consolidation is not known. To test this, it would be necessary to evaluate whether preventing posttraining spinogenesis, specifically in this region, disrupts memory consolidation.The transcription factor myocyte enhancer factor 2 (MEF2) negatively regulates spinogenesis in an activity-dependent manner and therefore provides a tool to address this question. For example, increasing MEF2 function decreases the number of dendritic spines and excitatory synapses in vitro (15) and blocks increases in spine density normally observed following repeated cocaine administration in rat medium spiny...

Region- and Layer-Specific Activation of the Higher Order Auditory Cortex Te2 after Remote Retrieval of Fear or Appetitive Memories

“…Spine remodeling and growth has been shown to occur in superficial layers during remote memory formation in mice (Lesburguères et al 2011;Vetere et al 2011;Xie et al 2014), and contextual fear conditioning has been shown to determine a memory-related activation of sparse neurons in layer II of several cortices in mice, which lasts for 2 months (Xie et al 2014). Taken together, past and the present data support the view that superficial layers represent key sites for memory processes.…”

New methods for understanding systems consolidation

“…These changes have no effect on learning but produce severe memory loss weeks later (Frankland et al 2001). Consistent with this finding, spine growth in the anterior cingulate and orbitofrontal cortex is necessary for remote memory formation (Lesburgueres et al 2011;Vetere et al 2011). Together, these studies indicate that the consolidation of recently formed memories depends on the ability of the neocortex to form new synaptic connections (Frankland and Bontempi 2005).…”

Systems Reconsolidation Reveals a Selective Role for the Anterior Cingulate Cortex in Generalized Contextual Fear Memory Expression

“…Such findings have led to the idea that the hippocampus serves a critical role in integrating information from a distributed cortical network representing various features of a memory, and that over time, the medial prefrontal cortex (including the ACC) gradually takes over this integrative role, allowing the memory to function independently of the hippocampus (Frankland and Bontempi, 2005). In support of this view, imaging studies have revealed sequential activity in area CA1 in the hippocampus and ACC for recent and remote time points after learning, respectively, in terms of immediate-early gene expression (Frankland et al, 2004), and dendritic spine growth (Vetere et al, 2011). This transition has been suggested to reflect systems consolidation, during which post-training hippocampal replay of episodic or detailed memory leads to memory trace reactivation in the cortex, promoting the development of a more schematic cortical representation (McClelland et al, 1995;Winocur et al, 2010).…”