Basal Forebrain Impairment: Understanding the Mnemonic Function of the Septal Region Translates in Therapeutic Advances

Abstract

The basal forebrain is one of the three major brain circuits involved in episodic memory formation together with the hippocampus and the diencephalon. The dysfunction of each of these regions is known to cause anterograde amnesia. While the hippocampal pyramidal neurons are known to encode episodic information and the diencephalic structures are known to provide idiothetic information, the contribution of the basal forebrain to memory formation has been exclusively associated with septo-hippocampal cholinergic signaling. Research data from the last decade broadened our understanding about the role of septal region in memory formation. Animal studies revealed that septal neurons process locomotor, rewarding and attentional stimuli. The integration of these signals results in a systems model for the mnemonic function of the medial septum that could guide new therapeutic strategies for basal forebrain impairment (BFI). BFI includes the disorders characterized with basal forebrain amnesia and neurodegenerative disorders that affect the basal forebrain. Here, we demonstrate how the updated model of septal mnemonic function can lead to innovative translational treatment approaches that include pharmacological, instrumental and behavioral techniques.

Association of Plasma Phosphorylated Tau With the Response to Neflamapimod Treatment in Patients With Dementia With Lewy Bodies

“…33,34 Our results in the TUG test (Figure 3B) and ISLT-Recognition (Figure 4), showing the most prominent treatment effect differences between plasma ptau181 strata, are instructive in that regard because both measures would be expected to be influenced by the cholinergic input from the medial septal nucleus of the basal forebrain to the hippocampus. 35…”

“…33,34 Our results in the TUG test (Figure 3B) and ISLT-Recognition (Figure 4), showing the most prominent treatment effect differences between plasma ptau181 strata, are instructive in that regard because both measures would be expected to be influenced by the cholinergic input from the medial septal nucleus of the basal forebrain to the hippocampus. 35 Recently, the results similar to ours with respect to the association of a plasma biomarker of AD copathology on treatment response to a novel agent were reported 36 with the PDE9 inhibitor, irsenontrine; in a 12-week, placebo-controlled phase 2 study in DLB, "amyloid-negative" patients (evidenced by a high plasma Aβ42/40 ratio) demonstrated a trend (p = 0.053) toward improvement in cognition, measured using the Montreal Cognitive Assessment, whereas no such trends were evident in "amyloid-positive" patients. Together with our results, these findings point to the potential utility of a plasma biomarker for underlying pathology to decrease patient heterogeneity either as a covariate or by excluding patients with a concomitant, and potentially confounding, pathology.…”

Beyond shallow feelings of complex affect: Non-motor correlates of subjective emotional experience in Parkinson’s disease

“…In particular, both film excerpts targeting Sadness recreated scenarios of personal or social loss. Overall, the non-motor manifestations in this cluster suggest a predominant dysfunction of the cholinergic basal forebrain complex and its connected cortex, implicated in tender and sad affiliative feelings [59,98], sleep regulation [99], and, together with the hippocampus, in episodic memory formation [100]. In particular, successful memory performance has recently been shown to rely on strong functional connectivity between the BF and insular cortex, a core area of socioemotional processing [101].…”

Recent advances in neural mechanism of general anesthesia induced unconsciousness: insights from optogenetics and chemogenetics

“…The basal forebrain (BF) is a heterogenous region composed of multiple areas, including substantia innominate, nucleus accumbens and ventral pallidum of the basal ganglia, bed nucleus of the stria terminalis, the preoptic area, the nucleus basalis of Meynert, the septal nuclei and diagonal band of Broca ( Tsanov, 2022 ). Cholinergic, glutamatergic and GABAergic neurons are the major neuronal populations in the basal forebrain ( Xu et al, 2015 ).…”