2. Relationship between alcohol, memory consolidation, and hippocampus
Evidence in several rodent models has shown that ethanol produces cognitive impairment in hippocampal-dependent tasks and that the damage varies according to the stage of development at which the rodent was exposed to EtOH and the dose (Table 3) (White et al., 2000; Reid et al., 2020; Mira et al., 2020). As brain development persists during childhood and adolescence in mammals, alcohol consumption is not only risky during the prenatal stages, but adolescence as well (Table 3). Furthermore, adolescence is usually the age for the start of alcohol consumption and abuse in humans (Mira et al., 2020) due to social enhancement and coping motives (Kuntsche et al., 2005). On the other hand, alcohol-related alterations in adult rodents are not conclusive. However, some experiments have reported cognitive impairment in non-spatial and spatial tasks in the Morris water maze as well as behavioral flexibility impairment (Matthews et al., 2020; Ho et al., 2022).
In addition, several experimental evidences demonstrate that alcohol consumption during gestation, young, and adult rodents produce physical changes such as a reduction in neuronal cell number, brain size, density and volume (Klintsova et al., 2007; Lee et al., 2015; Livy et al., 2003), neurodegeneration (Bird et al., 2018), and decreased neurogenesis (Ieraci and Herrera, 2007) that may explain cognitive impairment (Table 4). However, further investigation is needed.
Memory consolidation is one of the principal processes altered in cognitive impairment produced by alcohol. Memory can be divided into short-term and long-term memory. Short-term memory, called working memory, maintains current, albeit transient, representations of goal-relevant knowledge obtained by verbal and visual-spatial information (Kumar et al., 2020). Short-term memory is converted into long-term memory by a process called memory consolidation, which is enhanced by repetition and by adding several sensory modalities or adding emotional context (Tonegawa et al., 2018; Klinzing et al., 2019; Girardeau and Lopes-dos-Santos, 2021). Figure 1 provides an overview of the subdivisions of memory.
In addition, memory consolidation requires both hippocampus-dependent and non-hippocampus-dependent processes, but we will focus on the role of the hippocampus structure (Kibble and Halsey, 2015; Klinzing et al., 2019). The hippocampus is a bilateral structure, meaning that the brain has two hippocampi, which are located deep in the innermost fold of the temporal lobe (Figure 2a,b) (Stimac, 2022). It has a seahorse-like shape formed by the cornu ammonis (CA), further divided into four zones, namely, CA1, CA2, CA3, and CA4 (Mira et al., 2020). The hippocampus forms the hippocampal formation, which also includes the dentate gyrus (DG) and the subiculum. Together, these structures play important roles in learning and memory, and considering that the DG is one of the two sites for neurogenesis in the mature brain (Sokolowski and Corbin, 2012; Abbott and Nigussie, 2019). Hippocampus in mammals has a five-layered structure, consisting mainly of pyramidal cells that have both apical and basal dendrites. In contrast, the DG has a three-layered structure consisting mainly of granule cells that have only apical dendrites. Interneurons are a minority of neurons in the hippocampal formation, making up only 10-20% of the total, but they play a crucial role in regulating circuit-level signaling within the hippocampus due to their dense axonal arborization (Bird et al., 2018).
The hippocampus plays a relevant role in memory consolidation. In this brain region, multimodal sensory and spatial information from the entorhinal cortex via its principal trisynaptic circuit is processed and integrated (Figure 3) (Chao et al., 2020; Park et al., 2021). In this circuit the axons of layer II neurons of the entorhinal cortex project through the perforant pathway into the granule cells of the DG. Granule cell axons, termed mossy fibers, are projected into the mossy fiber pathway to stimulate pyramidal cells in the CA3 region of the hippocampus. Finally, the CA3 axons, called the Schaffer collaterals, project through the Schaffer collateral pathway to make excitatory synapses on more proximal regions of CA1 pyramidal cell dendrites. The major output of the hippocampus is through the pyramidal neurons in the CA1 region, which project to the subiculum before extending back to the entorhinal cortex. Both, CA1 and the subiculum, have projections into the fornix, primarily to the septal nuclei and the mammillary bodies; moreover, in this circuit backprojection pathways could serve to modulate information processing in
hippocampal CA1 (Xu et al., 2016; Martin, 2021).
As mentioned before, human and rodent brains have a resemblance in the anatomical organization and functional development, particularly in the hippocampal formation, which is illustrated in Figure 2. These similarities in memory function across mammalian species compel rodents as animal models (Clark and Squire, 2013). Furthermore, both humans and rodents manifest SWRs in the hippocampus when they are consolidating memory (Buzsáki, 2015).