Ricerc@Sapienza

Diabetes induces early sufferance in the cholinergic septo-hippocampal system, characterized by
deficits in learning andmemory, reduced hippocampal plasticity and abnormal pro-nerve growth factor
(proNGF) release from hippocampal cells, all linked to dysfunctions in the muscarinic cholinergic
modulation of hippocampal physiology. These alterations are associated with dysregulation of several
cholinergic markers, such as the NGF receptor system and the acetylcholine biosynthetic enzyme
choline-acetyl transferase (ChAT), in the medial septum and its target, the hippocampus. Controlled
and repeated sensory stimulation by electroacupuncture has been proven effective in counteracting
the consequences of diabetes on cholinergic system physiology in the brain. Here, we used a wellestablished
Type 1 diabetes model, obtained by injecting young adult male rats with streptozotocin, to
induce sufferance in the septo-hippocampal system.We then evaluated the effects of a 3-week treatmentwith
low-frequency electroacupuncture on: (a) the expression and protein distribution of proNGF
in the hippocampus, (b) the tissue distribution and content of NGF receptors in the medial septum,
(c) the neuronal cholinergic and glial phenotype in the septo-hippocampal circuitry. Twice-a-week
treatment with low-frequency electroacupuncture normalized, in both hippocampus and medial septum,
the ratio between the neurotrophic NGF and its neurotoxic counterpart, the precursor proNGF.
Electroacupuncture regulated the balance between the two major proNGF variants (proNGF-A and
proNGF-B) at both gene expression and protein synthesis levels. In addition, electroacupuncture
recovered to basal level the pro-neurotrophic NGF receptor tropomyosin receptor kinase-A content,
down-regulated in medial septum cholinergic neurons by diabetes. Electroacupuncture also regulated
ChAT content in medial septum neurons and its anterograde transport toward the hippocampus. Our
data indicate that repeated sensory stimulation can positively affect brain circuits involved in learning
and memory, reverting early impairment induced by diabetes development. Electroacupuncture could
exert its effects on the septo-hippocampal cholinergic neurotransmission in diabetic rats, not only by
rescuing the hippocampal muscarinic responsivity, as previously described, but also normalizing acetylcholine
biosynthesis and NGFmetabolismin the hippocampus.