Enhanced Sensitivity of the MRL/MpJ Mouse to the Neuroplastic and Behavioral Effects of Acute and Chronic Antidepressant Treatments

Enhanced Sensitivity of the MRL/MpJ Mouse to the Neuroplastic and Behavioral Effects of Acute and Chronic Antidepressant Treatments

Balu, Darrick T. Experimental and Clinical Psychopharmacology, Vol. 18 (1), Feb 2010, 71-77. doi: 10.1037/a0017295

Neurogenesis is a process that has been shown in research to continue throughout life. It is a general term that describes the complex process of cell generation, including proliferation of multipotent stem cells, differentiation into distinct cell subtypes, and the survival of cells for incorporation into cellular networks. In mammals, the particular sites for neurogenesis are the subventricular zone, which projects cells to the olfactory bulb, and the subgranular zone of the hippocampus. Small amounts of neurogenesis can also happen in the cerebellum and amygdala.

There are certain factors that modulate neurogenesis—these include growth factors, psychotropic systems, sex hormones, stress, exercise, etc.

Adult hippocampal generation has been implicated as a treatment for depression, which can cause degeneration of the hippocampal cells to begin with.

In this study, the first thing the researcher did was compare a newer method of quantifying neurogenesis, flow cytometry, to the older method of immunohistochemical methods. Basically, with flow cytometry, a chemical called S-bromo-deoxyuridine (BrdU) is injected into the brain. The brain cells actively take it up. After the animals used in this testing have been injected, they are sacrificed and sections are made of their brains. Under a microscope, the researcher can count the number of cells that are BrdU positive very quickly. In the old immunohistochemical methods, counting took much longer.

Three different kinds of manipulations revealed statistically similar effects of indication of  neurogenesis using both methods:

1.      Streptozotocin, which destroys the insulin-producing cells of the pancreas, was used to induce experimental type 1 diabetes in rats. Hippocampal cell proliferation was reduced by about 25 % in both methods.

2.      Administration of the toxin N-ethyl-N-(chloroethyl)-2-bromoben zylamine hydrochloride destroys noradrenergic cell bodies on the locus coeruleus and was used to deplete norepinephrine in the hippocampus and forebrain—8 days later cell proliferation in the hippocampus was reduced by about 30% in both cases.

3.      Chronic administration of somatic and pharmacological antidepressant treatments increases hippocampal neurogenesis. It takes about 5 days of electroconvulsive shock and 21 days of fluoxetine to see elevated hippocampal cell proliferation.

In the end, significant correlations existed between the brains of mice measured by immunohistochemical and flow cytometric methods

In the second part of this study, the researcher examined the behavioral and neurological responses of a special mouse strain, strain MRL/MpJ, to acute and chronic antidepressant treatments. This particular strain of mice shows speedier bodily healing times than other mice to injuries. They were measured against a control.

To begin with, tissue levels of these mice and the control mice were measured for serotonin and norepinephrine. As predicted because of their special healing abilities, these mice had significantly higher levels of serotonin in their hippocampi, frontal cortexes, amygdales, and brain stems than the control.

Next, the researcher used microdialyses to measure serotonin in the hippocampus, injected the mice with citaloprom, and observed. Both strains of mice had a large increase in the release of serotonin in the ventral hippocampi, but the MRL/MpJ mice’ serotonin levels increased 7 to 9 times the base level while the control strain increased 3 to 4 times.

The next test was a tail suspension test. In this test, mice are suspended by their tails from an elevated bar for several minutes. Usually, mice engage in escape-oriented behaviors, such as body jerks and leg kicks. These are followed by increasing periods of immobility. Antidepressant treatment reduces the time spent immobile, so the more sensitive mice strain should have a greater lessening of immobility time than the control. This did occur.

There are clinical limitations of current pharmacologic antidepressants. They usually take 2-6 weeks for effects to develop. Molecular and cellular adaptations require persistent drug exposure.

The general conclusions of this study are that the use of flow cytometry is effective compared to the old method of analysis. Also, there are differences in how the two mouse strains respond to antidepressants. This may have implications for other mammals, such as humans.