Motor activity is modulated via different neuronal circuits in rats with chronic liver failure than in normal rats

Abstract

The mechanisms by which liver failure alters motor function remain unclear. It has been suggested that liver disease alters the neuronal circuit between basal ganglia and cortex that modulates motor function. Activation of group I metabotropic glutamate receptors in the nucleus accumbens (NAcc) by injecting (S)-3,5-dihydroxyphenylglycine (DHPG) activates this circuit and induces locomotion We analysed by in vivo brain microdialysis the function of the circuits that modulate motor function in rats with liver failure due to portacaval shunt (PCS). We inserted cannulae in the NAcc and microdialysis probes in the NAcc, ventral pallidum (VP), substantia nigra pars reticulata (SNr), medio-dorsal thalamus (MDT), ventro-medial thalamus (VMT) or prefrontal cortex (PFCx). We injected DHPG in the NAcc and analysed extracellular neurotransmitters concentration in these areas. The results indicate that in control rats DHPG induces locomotion by activating the 'normal' neuronal circuit: NAcc --> VP --> MDT --> PFCx. In PCS rats this circuit is not activated. In PCS rats, DHPG injection activates an 'alternative' circuit: NAcc --> SNr --> VMT --> PFCx. This circuit is not activated in control rats. DHPG injection increases dopamine in the NAcc of control but not of PCS rats, and glutamate in PCS but not in control rats. DHPG-induced increase in dopamine would activate the 'normal' neuronal circuit, while an increase in glutamate would activate the 'alternative' circuit. The identification of the mechanisms responsible for altered motor function and coordination in liver disease would allow designing treatments to improve motor function in patients with hepatic encephalopathy.

Impairment of the Organization of Locomotor and Exploratory Behaviors in Bile Duct-Ligated Rats

“…It is described that animals that are subjected to this surgical model of type C HE develops liver failure, jaundice, portal hypertension, bacterial translocation, immune system dysfunction, hyperammonemia and low-grade encephalopathy [21]. Using this animal model we have obtained evidence that the biosynthetic machinery for transmitter GABA is disturbed [23], which may be of interest since GABAergic neurotransmission has been related to aberrations in the behavioral parameters that are normally associated with HE [12], [24].…”

Portosystemic hepatic encephalopathy model shows reversal learning impairment and dysfunction of neural activity in the prefrontal cortex and regions involved in motivated behavior

“…Perhaps the most frequently used is the portacaval shunt model, considered one of the best models of chronic minimal type B HE, 4 which corresponds to encephalopathy associated with a portosystemic shunt. Although portacaval-shunted rats have been found to experience difficulties when learning tasks, including passive and active avoidance and conditional discrimination tasks in the Y maze, [5][6][7] little research has focused on the learning deficits of these animals in the Morris water maze (MWM). [8][9][10] The goal of the present work was to evaluate spatial reversal learning in a rat model of portacaval anastomosis and to study the oxidative metabolism of various brain limbic system regions involved in memory via histochemical labeling of cytochrome oxidase (CO).…”

The Use of Microdialysis in the Study of Encephalopathies

“…Their results indicate that in control rats, DHPG induces locomotion by activating the normal neuronal circuit: NAcc --> VP --> MDT --> PFCx and in PCS rats this circuit is not activated but DHPG injection in PCS rats activates an alternative circuit: NAcc --> SNr --> VMT --> PFCx that is not activated in control rats. These experiments suggest that dopamine increase i n d u c e d b y D H P G w o u l d a c t i v a t e t h e n o r m a l n e u r o n a l c i r c u i t , w h i l e a n i n c r e a s e i n glutamate would activate the alternative circuit (Cauli et al, 2007).…”

“…Cauli et al (2007) demonstrated that the function of the circuits that modulate motor function in rats with liver failure due to portacaval shunt (PCS) is dependent on the kind of neurotransmission. They found this result by analyzing the function of the circuits that modulate motor function in rats with liver failure due to portacaval shunt (PCS) using in vivo brain microdialysis.…”