Amygdalar GABAergic-rich neural grafts attenuate anxiety-like behavior in rats

Abstract

Transplantation experiments have shown that neurologic deficits may be reversed by engrafting fresh tissue or engineered cells within dysfunctional neural circuitry. In experimental and clinical settings, this approach has provided insights into the pathology and treatment of neurologic diseases, primarily movement disorders. The present experiments were designed to investigate whether a similar strategy is feasible as a method to investigate, and perhaps repair, circuitry integral to emotional disorders. We focused on the amygdala, a macrostructure known to be involved in the expression of anxiety- and fear-related behaviors. GABAergic cell-rich suspensions were prepared from E17 rat lateral ganglionic eminence and engrafted bilaterally into the lateral and basolateral amygdaloid nuclei of young adult rats. After six weeks, increased numbers of GABAergic neurons were identified in the vicinity of the graft sites, and electron microscopy provided evidence for functional integration of transplanted cells. Rats with these grafts spent more time in the open arms of the elevated plus maze, consistent with an anxioloytic-like phenotype. These rats were also less sensitive to the unconditioned anxiogenic effects of light on the acoustic startle response, although fear-potentiated startle was not affected, suggesting that the grafts produced an attenuation of unlearned fear but did not affect acquisition of conditioned fear. Our results raise the possibility that distinct components of emotion can be modulated by strategic neural engraftment.

Long-lasting anxiolytic effect of neural precursor cells freshly prepared but not neurosphere-derived cell transplantation in newborn rats

“…Moreover, cells obtained from MGE could present discrepant results when transplanted as fresh or neurosphere cells. Recent studies have shown that cells derived from the sub regions of eminences were able to modify the anxiety behavior in transplanted animals increasing the GABAergic transmission and producing anxiolytic effects [5, 7]. In the present study, although animals transplanted with neurosphere cells did not present effects in anxiety-like behavior, animals grafted with MGE fresh cells presented a clear-cut anxiolytic-like behavior in the EPM test.…”

“…In the central nervous system, GABA-mediated inhibition is critical for controlling synaptic circuits involved in the modulation of anxiety [6]. Studies evaluating the anxiety behavior of animals transplanted with cells derived from the MGE [5] and LGE (lateral ganglionic eminence) [7] have shown that these cells can produce anxiolytic-like effects.…”

The HTR3A Polymorphism c. -42C>T Is Associated With Amygdala Responsiveness in Patients With Irritable Bowel Syndrome

“…Greater presynaptic expression of HTR3A on inhibitory GABAergic input to the amygdala is expected to result in greater GABAergic inhibition of the amygdala during serotonergic stimulation 42, 43 . Increased inhibitory GABAergic function in the amygdala via benzodiazepines 44 , micro-infusion of GABA A receptor agonists 45 or neuron-rich grafts 46 has been associated with decreased anxiety. These results suggest T carriers have enhanced amygdala 5-HT 3A expression and GABAergic function associated with decreased anxiety.…”

Differential Effect of Unilateral Amygdalar GABA<sub>A</sub> Receptor Agonist Injection on Low- and High-Anxiety Rats

“…Mice deficient in GAD65 exhibits increased anxiety-like responses in both the open field and elevated zero maze assays [38]. Rats with artificially elevated number of GABAergic neurons are found to spend more time in the open arms of the elevated plus-maze [39]. The level of GABA receptors containing α5 and γ1 subsunits is lower in the central and medial amygdala of high anxietyrelated behavior (HAB) mice than in mice with normal anxiety-like behavior (NAB).…”