Early-onset cortico-cortical synchronization in the hemiparkinsonian rat model.

Changes in synchronized neuronal oscillatory activity are reported in both cortex and basal ganglia of Parkinson's disease patients. The origin of these changes, in particular their relationship with the progressive nigrostriatal dopaminergic denervation, is unknown. Therefore, in the present study we studied interregional neuronal synchronization in motor cortex and basal ganglia during the development of dopaminergic degeneration induced by a unilateral infusion of 6-hydroxydopamine (6-OHDA) into the rat medial forebrain bundle. We performed serial local field potential recordings bilaterally in the motor cortex and the subthalamic nucleus of the lesioned hemisphere prior to, during, and after development of the nigrostriatal dopaminergic cell loss. We obtained signal from freely moving rats in both resting and walking conditions, and we computed local spectral power, interregional synchronization (using phase lag index), and directionality (using Granger causality). After neurotoxin injection the first change in phase lag index was an increment in cortico-cortical synchronization. We observed increased bidirectional Granger causality in the beta frequency band between cortex and subthalamic nucleus within the lesioned hemisphere. In the walking condition, the 6-OHDA lesion-induced changes in synchronization resembled that of the resting state, whereas the changes in Granger causality were less pronounced after the lesion. Considering the relatively preserved connectivity pattern of the cortex contralateral to the lesioned side and the early emergence of increased cortico-cortical synchronization during development of the 6-OHDA lesion, we suggest a putative compensatory role of cortico-cortical coupling.

Food cues and ghrelin recruit the same neuronal circuitry.

BACKGROUND: Cues that are associated with the availability of food are known to trigger food anticipatory activity (FAA). This activity is expressed as increased locomotor activity and enables an animal to prepare for maximal utilization of nutritional resources. Although the exact neural network that mediates FAA is still unknown, several studies have revealed that the medial hypothalamus is involved. Interestingly, this area is responsive to the anorexigenic hormone leptin and the orexigenic hormone ghrelin that have been shown to modulate FAA. However, how FAA is regulated by neuronal activity and how leptin and ghrelin modulate this activity is still poorly understood. OBJECTIVE: We aimed to examine how the total neuronal population and individual neurons in the medial hypothalamus respond to cue-signaled food availability in awake, behaving rats. In addition, ghrelin and leptin were injected to investigate whether these hormones could have a modulatory role in the regulation of FAA. DESIGN: Using in vivo electrophysiology, neuronal activity was recorded in the medial hypothalamus in freely moving rats kept on a random feeding schedule, in which a light cue signaled upcoming food delivery. Ghrelin and leptin were administered systemically following the behavioral paradigm. RESULTS: The food-predictive cue induced FAA as well as a significant increase in neural activity on a population level. More importantly, a sub-population of medial hypothalamic neurons displayed highly correlated identical responses to both ghrelin and FAA, suggesting that these neurons are part of the network that regulates FAA. CONCLUSION: This study reveals a role for ghrelin, but not leptin, signaling within medial hypothalamus in FAA on both a population level and in single cells, identifying a subset of neurons onto which cue information and ghrelin signaling converge, possibly to drive FAA.

Recovery of neuroendocrine cells after injury in the aging brain of a mollusc.

Recovery after crush of neuroendocrine caudodorsal cells (CDCs) in the aging brain of the mollusc Lymnaea stagnalis, was determined as a measure of neuronal plasticity. Neuronal plasticity was determined in differently aged animals containing intact (young: 170 days) or morphologically and physiologically degraded (middle-aged: 305 days and old: 443 days) CDCs. Branching patterns and electrical and chemical connectivity and afterdischarge activity of CDCs were studied. Immediately after crush, electrical coupling and chemical transmission were absent. In all age groups partial recovery occurred within about 20 days. CDCs in old animals exhibited restricted recovery of electrical coupling and enhanced recovery of chemical transmission. In young and middle-aged animals normal afterdischarges occurred from day 8 on. In old animals abnormal afterdischarges occurred starting at day 0, becoming normal by day 12 after crush. Recovery of CDC branching was partial in all age groups. It is concluded that in the aging brain recovery of CDCs after injury does occur but is differentially restricted. Our results suggest that senescent degraded neurons still possess a considerable degree of plasticity.

cAMP and excitability in neuroendocrine cells during reproductive senescence.

Excitability changes during reproductive senescence were investigated in the neurosecretory caudodorsal cells (CDCs) that control egg laying in the mollusc Lymnaea stagnalis. CDCs in the isolated central nervous system (CNS) were exposed to different discharge inducing treatments. Senescent CDCs (of animals 8 weeks after laying their last egg mass) and inhibited (I-) state CDCs (of egg-laying (EL) animals) were used. We showed that senescent and I-state CDCs closely resemble each other electrophysiologically. Electrical stimulation did not induce an afterdischarge in either type of CDC but exposure to release products of CDCs from EL animals or to saline with high potassium concentration did induce discharge activity. Also, 8-chlorophenylthio (8-CPT)-cAMP (10(-5) M) induced discharge activity. Exposure to the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) (10(-3) M) or to the adenylate cyclase activator Forskolin (10(-4) M), restored afterdischarge induction by electrical stimulation. Application of IBMX (10(-3) M) and Forskolin (10(-4) M) together induced discharges in the absence of electrical stimulation. Our results suggest that in senescent CDCs changes in the intracellular cAMP pathway may underlie afterdischarge failure.

Excitability and branching of neuroendocrine cells during reproductive senescence.

In the mollusc Lymnaea stagnalis, neuroendocrine caudodorsal cells (CDCs) were studied physiologically and morphologically from egg layers (EL) (aged 154-400), and animals 4 weeks (CEL-4) (342-455 days), and 8 weeks (CEL-8) (477-660 days) after production of their last egg mass. After recording chemical transmission, electrical coupling and stimulation induced afterdischarges (ADs), CDCs then were filled with Lucifer Yellow. Based on the axonal branching revealed by Lucifer Yellow, CDCs were classified as extensively, moderately, or minimally branched. In EL-CDCs, induction of AD activity, which normally (9) precedes egg-laying, only was initiated in the resting state. CEL-4 CDCs exhibited ADs whereas CEL-8 CDCs did not. CEL-8 CDCs exhibited significantly reduced chemical and electrical transmission, and CEL-4 CDCs did not differ from resting state EL-CDCs. CDC branching was significantly reduced with both increasing age and declining egg-laying. Minimally branched CDCs most frequently failed to exhibit an AD and exhibited reduced electrical coupling. We conclude that both physiology and morphology of CDCs are related to age and reproductive state.

Multiple synaptic connections of a single neuron change differentially with age.

The efficacy of chemical synaptic connections of a single identified interneuron with different types of follower neurons was studied throughout the adult life of the pond snail Lymnaea stagnalis. Simultaneous intracellular recordings were made from the interneuron RPeD1 and its follower neurons in isolated CNS preparations from animals of different age groups (3-18 months of age). The presence of postsynaptic responses to RPeD1 action potentials was tested. With increasing age, the number of A-group neurons that was found with a response to evoked RPeD1 action potentials decreased, yet the number of HIJK-group neurons responding to RPeD1 input increased. The number of G-group neurons and the number of individual neurons VD2/3 and VD4 with RPeD1 input did not differ significantly between age groups. However, there was variability in the presence of responses in these individual neurons. Thus, synaptic connections of the single interneuron RPeD1 change differentially throughout the adult life of L. stagnalis. Within the A-group we found indications that changes in RPeD1 input apply to the entire A-group. In the A-group neurons changes in several electrical properties could not account for the observed age-related changes in the number of neurons responding to RPeD1 action potentials.

Atrophy and degeneration of peptidergic neurons and cessation of egg laying in the aging pond snail Lymnaea stagnalis.

The morphology of the neuroendocrine caudodorsal cells (CDCs), which are involved in the regulation of female reproduction in the pond snail Lymnaea stagnalis, was studied in young (200 to 234 days of age) and old (400 to 500 days) animals. Lucifer Yellow fills of ventral CDCs showed that in young animals ventral CDCs branch ipsilaterally as well as contralaterally in the cerebral commissure. In old animals these branches were reduced at different degrees and in some cases even lacking completely, leaving only an axon crossing the commissure. Immunocytochemical stainings with antibodies against CDC peptides (CDCH-I and alpha CDCP) corroborated the finding that ventral CDCs degenerate. Among the other types of CDCs (dorsal, lateral), degeneration was found as well. The immunocytochemical findings showed that in old animals the axon terminals of the CDCs were strongly stained, indicating that they are packed with secretory vesicles containing peptides. It was also found that these darkly stained, peptide-containing axon terminals protruded into the perineurium. These findings suggest that accumulation of peptides in the terminals of the CDCs of old animals may be due to the impaired release. The relationship between atrophy and degeneration of CDCs and cessation of egg-laying activity in Lymnaea is discussed.

Degeneration of CDCs and egg laying in the pond snail Lymnaea stagnalis.

In the pond snail Lymnaea stagnalis egg laying is induced by multiple peptides, which are released by the neuroendocrine caudo-dorsal cells (CDCs). Egg laying in Lymnaea starts at about 50 days and increases initially with age to decreases again at an age of about 250 days. From that age on, the total number of animals that stop egg laying increases with age. The maximum age of Lymnaea is about 660 days. Lucifer Yellow fills of individual ventral CDCs showed reduced branching patterns in old animals. Immunocytochemical stainings demonstrated degeneration in ventral, dorsal and lateral CDCs. In animals that had stopped egg laying, CDCs could still be electrically activated. Regeneration studies after crushing the cerebral commissure showed that in old animals CDCs still can regenerate connections in the cerebral commissure. The properties of CDCs in old animals are discussed in relationship with possible mechanisms of cessation of egg laying in Lymnaea.

Age-related changes in junctional and non-junctional conductances in two electrically coupled peptidergic neurons of the mollusc Lymnaea stagnalis.

Age-related changes in electrotonic coupling ratio of two identified neurons in Lymnaea stagnalis were studied together with the underlying changes in the steady-state conductance properties of the network. Two phases were distinguished in the development of coupling ratio across lifespan. During the first phase (age of 3-13 months), coupling ratio decreased from decreased from 60% to 30%. The second phase (age 13-20 months) was characterized by an increase in coupling ratio. Values of up to 60% were reached again in the oldest animals. Voltage clamp measurements showed that the biphasic trend of the age-related changes in coupling ratio is paralleled by changes in conductance properties of the junction between VD1 and RPD2. During the first phase junctional conductance decreased, whereas during the second phase junctional conductance increased. In addition to the decrease in junctional conductance, a growth-related increase in non-junctional conductance of VD1 and RPD2 contributed to the decrease in coupling ratio observed during the first phase. Thus our results indicate that in Lymnaea junctional connections between neurons may undergo considerable and discontinuous changes after sexual maturation. In addition to these changes in steady-state electrical properties, indications were obtained that age-related changes of kinetically slower conductance(s) may occur in the non-junctional membrane of VD1 and RPD2.

Recovery of damage in a molluscan nervous system is impaired with age.

In the mollusc Lymnaea stagnalis recovery of the tentacle withdrawal reflex after peripheral nerve damage is delayed with age. Indications were obtained that this delay is due to impairment of recovery of central synaptic connections.

Age-related decrease in electrical coupling of two identified neurons in the mollusc Lymnaea stagnalis.

Electrophysiological characteristics of two identified giant electrotonically coupled neurosecretory cells in the central nervous system of the mollusc Lymnaea stagnalis were studied in mature animals of different age. The coupling coefficient of the neurons decreased considerably with age. The possibility that the decrease is due to an increase in the junctional resistance between the cells is discussed.