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Tesi etd-08102020-153357

Thesis type
Tesi di laurea magistrale
Analysis of central nervous system circuits involved in the elaboration of nociceptive stimuli and memories associated to fear in HSAN V mouse model.
Corso di studi
relatore Prof. Cattaneo, Antonino
relatore Prof.ssa Capsoni, Simona
Parole chiave
  • pain
  • nociception
  • circuitry
  • ngf
  • r100w
Data inizio appello
Secretata d'ufficio
Data di rilascio
Riassunto analitico
Hereditary sensory and autonomic neuropathy type 5 (HSAN V) is an autosomal recessive disorder. It is characterized by the loss of pain perception due to a mutation in the NGF gene. Patients with this mutation have a strong reduction in peripheral non-myelinated C fibers. Furthermore, nerve fibers positive for receptors responsive to thermal and nociceptive stimuli are absent or substantially reduced in homozygous and heterozygous subjects. From a cognitive point of view, subjects appear normal. To better investigate this disease and the effect of this NGF mutation on the nervous system, a mouse model for the point missense mutation R100W in the mature protein of NGF (NGF R100W) was generated. This model was generated through knock-in of the human mutated NGF gene into the NGF genic locus of the mouse. As the homozygote NGF R100W/R100W mouse dies in the first 30 days of life, the studies are focused on the heterozygote NGF R100W/wt mouse. The heterozygote mouse has proved to be a good model as it reflects many of the clinical features of human patients affected by the disease. In particular, the NGF R100W/wt mouse does not show deficits in working and spatial memory.
Testing the mouse for Pavlovian fear conditioning has shown it has a higher threshold for the pain-inducing stimulus (as expected) with respect to the control, but interestingly it shows an impairment within the recall phase, as it displays a reduced freezing response. This indicates that the mouse is not able to create this specific type of pain-related associative memory. Furthermore, the model has a normal innate fear response. This means that somehow the mouse is not able to perceive (or to remember) the noxious stimulus as such. To understand which part of the central circuitry is impaired by the NGFR100W mutation, I started to investigate the brain areas involved during fear conditioning and during the recall of fear memory (e.g. amygdala, medial prefrontal cortex, hippocampus). After the recall phase, the brains were processed. I used immunohistochemistry to identify the activated neurons. Furthermore, actual evidence demonstrates that the local inhibitory microcircuitry within some of these brain areas involved in fear conditioning (e.g amygdala) act as important regulators of the activity and the plasticity of projecting neurons. For this reason, I investigate the density of the most represented GABA-ergic interneuron populations in these areas (such as parvalbuminergic interneurons and somatostatin positive interneurons).
The density of these cellular populations has been investigated in the NGF R100W mouse and the control mouse that is the knock-in mouse for the wild type human NGF (NGF wt/wt).