Enhanced Presynaptic Neurotransmitter Release in the Anterior Cingulate Cortex of Mice with Chronic Pain

Abstract

The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in learning and memory. Recent studies show that painful stimuli activate the prefrontal cortex and that brain chemistry is altered in this area in patients with chronic pain. Components of the CNS that are involved in pain transmission and modulation, from the spinal cord to the ACC, are very plastic and undergo rapid and long-term changes after injury. Patients suffering from chronic pain often complain of memory and concentration difficulties, but little is known about the neural circuitry underlying these deficits. To address this question, we analyzed synaptic transmission in the ACC from mice with chronic pain induced by hindpaw injection of complete Freund's adjuvant (CFA). In vitro whole-cell patch-clamp recordings revealed a significant enhancement in neurotransmitter release probability in ACC synapses from mice with chronic pain. Trace fear memory, which requires sustained attention and the activity of the ACC, was impaired in CFA-injected mice. Using knock-out mice, we found that calmodulin-stimulated adenylyl cyclases, AC1 and/or AC8, were crucial in mediating the long-lasting enhanced presynaptic transmitter release in the ACC of mice with chronic pain. Our findings provide strong evidence that presynaptic alterations caused by peripheral inflammation contribute to memory impairments after injury.

Presynaptic and Postsynaptic Amplifications of Neuropathic Pain in the Anterior Cingulate Cortex

“…injury Zhao et al, 2006). Second, AC1 and AC8, two major forms of calcium-stimulated ACs, are critical for chronic pain in animal models including neuropathic pain (Wei et al, 2002;Vadakkan et al, 2006).…”

“…Coronal brain slices (300 m) at the level of the ACC were prepared using standard methods Zhao et al, 2006). Slices were transferred to submerged recovery chamber with oxygenated (95% O 2 and 5% CO 2 ) artificial CSF containing (in mM) 124 NaCl, 2.5 KCl, 2 CaCl 2 , 1 MgSO 4 , 25 NaHCO 3 , 1 NaH 2 PO 4 , and 10 glucose at room temperature for at least 1 h. Experiments were performed in a recording chamber on the stage of a BX51W1 microscope equipped with infrared differential interference contrast optics for visualization.…”

Predicting Aversive Events and Terminating Fear in the Mouse Anterior Cingulate Cortex during Trace Fear Conditioning

“…Convergent evidence from mouse studies in our laboratory has shown that the anterior cingulate cortex (ACC) is involved in trace fear conditioning (Zhao et al, 2005(Zhao et al, , 2006Wu et al, 2008;Steenland et al, 2010). It has been reported that calcium/ calmodulin-dependent protein kinase IV overexpressing mice have enhanced synaptic potentiation (long-term potentiation) in the ACC and increased acquisition of trace fear (Wu et al, 2008;Steenland et al, 2010).…”

“…It has been reported that calcium/ calmodulin-dependent protein kinase IV overexpressing mice have enhanced synaptic potentiation (long-term potentiation) in the ACC and increased acquisition of trace fear (Wu et al, 2008;Steenland et al, 2010). In addition, mice with deficits in ACC synaptic plasticity due to either FMR1 knockout or chronic pain also have deficits in trace fear conditioning (Zhao et al, 2005(Zhao et al, , 2006. Studies in mice have shown that c-fos is elevated in the ACC following trace fear conditioning and that removal of the ACC impairs trace but not delay fear conditioning (Han et al, 2003).…”

Alteration of cingulate long-term plasticity and behavioral sensitization to inflammation by environmental enrichment

“…In addition to the roles of the ACC in memory, processing at this level also plays a key role in regulating central nervous system responses to peripheral and central injuries (Davis et al 1997;Zhuo 2004). For example, peripheral inflammation caused enhanced presynaptic glutamate release (Zhao et al 2006) as well as the up-regulation of postsynaptic NR2B (Wu et al 2005b). Digit amputation results in bilateral plastic neural changes in the ACC, including an increase in immediate early gene expression, such as c-fos, egr-1, and CREB , and increased electrophysiological responses (Wei et al 2001;Wu et al 2005a).…”