Mark Chachich

Both medial prefrontal and amygdala central nucleus lesions abolish heart rate classical conditioning, but only prefrontal lesions impair reversal of eyeblink differential conditioning

Rabbits with lesions of either medial prefrontal cortex (mPFC) or amygdala central nucleus (ACN) were compared with sham-lesioned animals during differential and reversal classical conditioning of the eyeblink (EB) and heart rate (HR) response. Lesions of the mPFC, but not ACN, produced a severe impairment in EB reversal conditioning, but neither lesion affected original discrimination. However, both mPFC and ACN lesions produced a severe attenuation of accompanying HR decelerations during both initial differentiation and reversal. These results suggest that mPFC processing of Pavlovian conditioning contingencies affects not only the autonomic component of learning but preservative somatomotor conditioning as well, whereas ACN processing affects only the autonomic component.

Amygdala-prefrontal interactions and conditioned bradycardia in the rabbit.

Damage to the amygdala or medial prefrontal cortex (mPFC) produces deficits in learned autonomic adjustments. Whether connections between these 2 structures are necessary for acquiring classically conditioned heart rate (HR) decelerations was studied. Connections between them were interrupted by unilateral lesions of the mPFC and amygdala, but on opposite sides of the brain. One experiment focused on the mPFC and amygdala central nucleus and a second on the mPFC and amygdala basolateral complex. Bilateral lesions of either structure disrupted the HR conditioned response. The response of the 2 crossed lesioned groups also was smaller than that of the sham-operated and unilateral lesioned groups, but significant conditioned stimulus-evoked bradycardia occurred in both, suggesting that although interactions between the amygdala and mPFC may normally occur during associative emotional responding, these connections are not necessary for the acquisition of conditioned bradycardia.

The role of claustrum in Pavlovian heart rate conditioning in the rabbit (Oryctolagus cuniculus): anatomical, electrophysiological, and lesion studies.

The role of the claustrum in Pavlovian heart rate (HR) conditioning was studied in the rabbit (Oryctolagus cuniculus) by (a) mapping claustral projections to the prefrontal cortex (PFC), (b) recording claustral single-unit discharge to sensory stimulation and conditioning stimuli during HR conditioning, and (c) assessing the effects of claustral damage on HR conditioning. Contralateral and ipsilateral claustral projections to the PFC were found. Claustral cells responded to nonsignal stimulation with increased discharge and also showed conditioned stimulus-evoked increases in discharge during Pavlovian HR conditioning. Moreover, claustral lesions diminished the magnitude of the HR-conditioned response without affecting the cardiac-orienting response to the conditioned stimulus or the cardiac-unconditioning response to the unconditioned stimulus, suggesting a role for the claustrum in associative learning.

Antagonism of a PCP Drug Discrimination by Hallucinogens and Related Drugs

Drugs such as PCP and MK-801 can cause psychotic reactions in humans by antagonizing NMDA receptors. This action is ultimately toxic to certain cortical neurons and may be one mechanism underlying neurodegenerative diseases, including schizophrenia. It has been reported that hallucinogens such as LSD, DOM, and DOI can block the neurotoxic effects of NMDA antagonists, possibly by activating inhibitory 5-HT2A receptors on GABAergic interneurons that normally inhibit glutamatergic projections to the retrosplenial and cingulate cortexes. The purpose of this experiment was to determine the extent to which similar drugs might also alter the behavioral effects of one NMDA antagonist, PCP. Rats were trained to discriminate this compound (2.5 mg/kg) from saline and were then given a series of antagonist tests. It was found that LSD (0.32 mg/kg) and DOM (4.0 mg/kg) blocked the PCP cue completely; DMT (8.0 mg/kg) and a structural congener of LSD, lisuride (LHM; 0.4 mg/kg), blocked the effects of PCP partially. The 5-HT/DA antagonists spiperone and ritanserin had no effect on the PCP cue. These data suggest that LSD, DOM, and, less effectively, DMT and LHM can block the behavioral as well as the neurotoxic effects of NMDA antagonists most likely through agonist actions at 5-HT2 receptors.

Medial prefrontal lesions attenuate conditioned reflex facilitation but do not affect prepulse modification of the eyeblink reflex in rabbits

Abstract. Conditioned reflex facilitation occurs when the amplitude of the eyeblink (EB) unconditioned reflex (UR) is increased as a result of prior pavlovian conditioning. Prepulse modification of the EB reflex is produced by preceding the unconditioned stimulus (US) by a brief low-level neutral stimulus. This study examined both conditioned EB facilitation and prepulse modification in rabbits with either medial prefrontal (mPFC) lesions or sham lesions. Conditioned reflex facilitation was assessed by comparing EB UR amplitude prior to and after pavlovian EB conditioning. Animals that received CS/US paired presentations showed evidence of conditioned reflex facilitation, but animals with unpaired training did not. However, this increase in EB UR magnitude in the paired groups was smaller in animals with mPFC lesions, compared to those with sham lesions. In two subsequent experiments different groups of sham and lesion animals received an intense burst of white noise preceded by tones with different interstimulus interval durations to assess prepulse modification. Unlike conditioned facilitation, prepulse modification was unaffected by mPFC lesions.

Characterization of Single-Unit Activity in the Mediodorsal Nucleus of the Thalamus during Expression of Differential Heart Rate Conditioning in the Rabbit

Much recent evidence has shown that the thalamic-prefrontal axis is involved in Pavlovian conditioning in rabbits. However, while single cell activity in the prefrontal cortex has been previously studied during classical conditioning in rabbits, that of its thalamic projection nucleus, the mediodorsal (MD) nucleus, has not. Consequently, in the present research we recorded neuronal activity from individual cells in MD during expression of conditioned bradycardia in rabbits that received differential Pavlovian conditioning in which tones served as conditioned stimuli and periorbital shock served as unconditioned stimuli. The pattern of firing in MD was similar to that evoked in the medial prefrontal cortex (mPFC). Of 84 cells sampled, approximately 35% showed CS-evoked activity. Ninety percent of these cells showed increases in activity, while the remainder were biphasic, showing an initial increase followed by a decrease. Also, like the mPFC, some cells showed initial increases, which declined during CS presentation, while others showed gradual increases which reached their maximum at CS offset. Also some cells were responsive to the CS+ and others to the CS-. Thus, MD cells, like mPFC cells, are somewhat heterogenous with regard to responding to conditional stimuli, although, unlike the mPFC, no strictly inhibitory cells were found.

Role of dyslipidemia and AGE/ALE formation in the progression of nephropathy and retinopathy in STZ-diabetic rats

Abstract We hypothesized that the beneficial effects of a variety of pharmacological agents on the progression of diabetic complications were mediated by a common pathway limiting the formation of advanced glycation and advanced lipoxidation end products (AGEs/ALEs) on protein. We studied the effects of the AGE/ALE inhibitor pyridoxamine (PM), the antioxidant vitamin E (VE) and the ACE inhibitor enalapril (EP) on the development of nephropathy and retinopathy in STZ-induced diabetic rats over 29 weeks. Blood glucose and glycohemoglobin were similar in all diabetic groups. Plasma lipids rose continuously in diabetic animals and only PM significantly attenuated this increase. Early nephropathy was indicated by increased plasma creatinine, and urinary albumin, protein and TGF-β excretion in untreated rats. While all interventions limited renal damage to some extent, PM was the most effective, although the increased expression of renal laminin β1 and fibronectin mRNA was normalized by all therapies. Measurement of retinal damage (acellular capillaries, vascular basement membrane-associated laminin) showed that only PM significantly limited signs of early retinopathy in diabetic rats. Only PM limited the increases in the AGE/ALEs in renal and retinal tissue, and in skin collagen, of diabetic rats. Our results suggest that limiting both dyslipidemia and AGE/ALE formation is required for maximum protection of renal and retinal function in the STZ-diabetic rat.