Brain areas involved in different modes of memory

A healthy and stable memory function consists of three distinct stages: acquisition, consolidation and retrieval. Acquisition describes the perception of short-term storage of novel information therefore includes sensory processes and STM. The transformation of this novelty, thus STM, into stable knowledge, thus LTM, is termed consolidation while memory retrieval is commonly known as ”remembering”. Memory can also be classified into subtypes. This classification is in general well accepted and evidence from patients with different neuroanatomical symptoms indicate that distinct brain areas are involved in the respective forms and stages of memory. The most commonly known case is patient H.M. who was suffering from a severe epilepsy in the mid 1950s. In order to ameliorate the epileptic seizures, the hippocampus and adjacent regions of the temporal lobe were bilaterally removed via surgery (Scoville and Milner, 1957). Although this particular treatment did reduce the pathology, it led to a significant loss of memory func-tions in H.M. Interestingly, H.M. had a relatively stable episodic memory for events before his surgery and could remember new information for several seconds and even minutes, though he completely lacked the ability to store these information for a longer period of time. Despite this anterograde amnesia, H.M. was fully capable of learning new tasks though could not recall doing that certain task ever before. Thus, while implicit memory workedfine as well as the acquisition and retrieval of explicit memory, H.M. specifically lacked the ability to consolidate explicit mem-ory. Findings from H.M. indicated that the hippocampus and temporal lobe are crucial for the formation of new explicit memory. Data from other patients with neuroanatomical disturbances

and more recent data using novel approaches for real-life imaging in vertebrates could confirm thesefindings and in addition led to the identification of a number of brain regions involved in certain modes of memory (Kandel, 2013).

A

Anterior Cingulate Cortex

Amygdala Hippocampus

B

Cingulate cortex

Hippocampus

Figure 1.8–Location of the ACC and hippocampus in human and mouse brains:

A)Sagittal section of a human brain showing the ACC (blue, left) in the frontal lobe below the pre-frontal cortex and frontal sections displaying the hippocampus (red, right) in the medial temporal lobe. Graphics were modified from Kandel (2013).

B)Sagittal sections of a mouse brain showing the cingulate cortex (yellow) and the hippocampus (red). The anterior part of the cingulate cortex (dashed red lines) is considered as the mouse ACC. Graphic modified from Franklin and Paxinos (1997).

The anterior cingulate cortex (ACC) is a part of the frontal lobe located below the pre-frontal cor-tex and is partially surrounding the corpus callosum in the human and mouse brain alike (see figure 1.8). In human, the ACC shows extensive connections with the hippocampus, amygdala, prefrontal cortex, anterior insula, and the nucleus accumbens indicating its broad impact on cognition but also autonomic functions (Bush et al., 2000; Kandel, 2013). Based on neuroimaging studies and data from patients with lesions inside the ACC, this brain region is most commonly

linked to error detection and evaluation, reward prediction, decision making, empathy, impul-sity and emotion such as aggression (Bubenzer-Busch et al., 2015; Carter et al., 1999; Ende et al., 2016; Lockwood et al., 2015; Nelson et al., 2015; Oli´e et al., 2015). The anatomical linkage between the ACC and regions involved in memory function like the hippocampus and the pre-frontal cor-tex, however, indicate its role in memory as well. In fact, several studies could confirm a role of the ACC in learning and memory including the formation of episodic and spatial memory or retrieval of semantic memory (Cazalis et al., 2011; Giannakopoulos et al., 2000; Seo et al., 2015). Further evidence for a role of the ACC in memory function was found by Frankland et al., since gene expression analysis upon contextual fear conditioning and behavior tests following a specific anesthetic inactivation of the ACC clearly demonstrated its importance for associative memory. Disruptions within the ACC were implicated in depression, schizophrenia and bipo-lar disorder but also in mild cognitive impairment and AD (Giannakopoulos et al., 2000; Kandel, 2013; Nelson et al., 2015; Seo et al., 2015; Tekin et al., 2001).

CA1

EC

Sub

DG CA2

CA3

PrS PaS

Perforant pathway

mossy fiber Schaffer collaterals

Figure 1.9–Scheme of the hippocampal for-mation:

The hippocampal regions (DG, CA3, CA2, CA1) receive their input from the entorhinal cor-tex (EC) via the perforant pathway. Signal-ing within the hippocampus is mainly unidirec-tional through mossyfibers and Schaffer collat-erals. Sub: Subiculum; PaS: Parasubiculum; PrS:

Presubiculum. Graphic adapted from Kandel (2013).

The hippocampal formation, one of the brain regions removed in patient H.M., is located within the medial temporal lobe and reminds of the shape of a seahorse when dissected (seefigure 1.8, p.18) (Andersen et al., 2007). It consists of the hippocampal regions cornu ammonis (CA) and dentate gyrus (DG), and the subiculum connecting the hippocampus with the entorhinal cortex via the perforant pathway (seefigure 1.9). While the developing hippocampus signals bidirec-tionally, the adult hippocampus mainly functions unidirectional, signaling from the DG through the different CA regions (Shi et al., 2014). The major input is thereby received by the DG from the entorhinal cortex. The important role of the hippocampus in learning and memory is nowadays

2011; Kandel, 2013). The DG is one of the rare sites in the mammal brain where neurogenesis occurs throughout maturity (Gage, 2000). Thereby, neuronal progenitor cells within the sub-granular zone of the DG proliferate and mainly differentiate into dentate granule cells (Cameron et al., 1993). This synthesis of new neurons plays an important role in DG-dependent memory, including pattern recognition, temporal separation of acquired memory, or memory remodeling (Aimone et al., 2009; Cao et al., 2004; Deng et al., 2009). This effect on memory function seems to be specific for certain modalities as inhibition of adult neurogenesis impairs some but not all hippocampus related memories (Shors et al., 2002). These memory functions also include spatial memory, associative memory, and explicit sequential learning, strongly depending on the CA1 and CA3 region which are required for both acquisition and retrieval of learned information (Farovik et al., 2010; Montgomery and Buzs´aki, 2007; Sakaguchi et al., 2015).