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).