Potential mechanisms of effects of endogenous neuromodulators on the interdependent activity of neurons in various nuclei of the basal ganglia

A possible mechanism of influence of neuromodulators on interdependent activity of neurons in the diverse basal ganglia nuclei is suggested. According to modulation rules, an activation of postsynaptic Gs- or Gq/11-(Gi/0-) protein coupled receptors promotes induction of long-term potentiation (depression) of excitatory inputs to different neurons and augmentation (lowering) of their activity; an activation of presynaptic Gs- or Gq/11-(Gi/0-) protein coupled receptors promotes a rise (decrease) of release of GABA and co-peptides from striatal terminals and glutamate release from subthalamic terminals in the globus pallidus and output nuclei. It follows from the modulation rules that, since identical receptors are present on striatal neuron and their axon terminals, effects of neuromodulator action in diverse basal ganglia nuclei can be summarized. Neuromodulators released from striato-nigral and striato-pallidal fibers could promote interdependent activity of neurons in "direct" and "indirect" pathways through the basal ganglia due to convergence of these fibers on cholinergic interneurons and pallido-striatal cells.     

Protective effect of hypothermia during ischemia in neural cell cultures

Hypothermia offers protection from the effects of ischemia in small animals. We have recently shown that similar to small animals, hypothermia may also be protective in an astrocytic model of simulated ischemia in cell culture. This study was designed to look at the protective effects of hypothermia in cultures of cerebellar granular (glutamatergic) and cortical (GABAergic) neurons. We used LDH release into the medium as an indicator for neuron damage. Experiments were all done in sister cultures, in groups of six cultures at two temperatures (37 and 32 degrees Celsius). The duration of ischemia was three hours in cerebellar granular neuronal cell cultures and six hours in cortical neurons. LDH release was measured immediately after the insult. Hypothermia protected both granular and cortical neurons. In granular cells, LDH release was 62+/–18 at 32 degrees and 212+/–15 at 37 degrees (p=0.02). Cortical neurons showed LDH release of 15+/–2 at 32 degrees and 32+/–2 at 37 degrees (p=0.005). Our study suggests that similar to astrocytes, the protective effects of hypothermia are evident in neuronal cell cultures from the cerebellum and the cerebral cortex. Cell culture systems should prove useful techniques in understanding mechanisms of hypothermic protection during simulated ischemia in neurons from different sites.     

A role of the basal ganglia in the occurrence of visual hallucinations (a hypothetical mechanism)

A hypothetical mechanism of the basal ganglia involvement in visual hallucinations is proposed. According to this mechanism, hallucination is the result of modulation of the efficacy of corticostriatal synaptic inputs and changes in spiny cell activity due to the rise of striatal dopamine concentration (or due to other reasons). These changes cause an inhibition of neurons in the substantia nigra pars reticulata and subsequent disinhibition of neurons in the superior colliculus and pedunculopontine nucleus (including its cholinergic cells). In the absence of afferentation from the retina this disinhibition leads to activation of neurons in the lateral geniculate nucleus, pulvinar and other thalamic nuclei projecting to the primary and highest visual cortical areas, prefrontal cortex, and also back to the striatum. Hallucinations as conscious visual patterns are the result of selection of signals circulating in several interconnected loops each of which includes one of above mentioned neocortical areas, one of thalamic nuclei, limbic and one of visual areas of the basal ganglia, superior colliculus and/or pedunculopontine nucleus. According to our model, cannabinoids, opioids and ketamine may lead to hallucinations due to their promotional role in the LTD of cortical inputs to GABAergic spiny cells of striatal striosomes projecting to dopaminergic neurons, disinhibition of the lasts, and increase in striatal dopamine concentration.     

Organization of the Connections between the Parietal Associative Zone and the Primary Sensory Zones in the Cat Neocortex

In acute experiments on cats, we studied the impulse activity of 262 neurons of the parietal associative zone (PAZ, field 5). Among them, 129 cells [100 silent units and 29 units generating background activity (BA)] were identified as output neurons, while 133 cells with the BA were interneurons of the intrinsic cortical neuronal circuits. Electrical stimulation of the primary visual, auditory, or somatosensory cortices evoked no impulse responses in silent output PAZ neurons, while output neurons with the BA and interneurons (more than 65 and 80% of the cell units, respectively) generated clear responses (more frequently, phasic). Stimulation of the auditory and visual cortices exerted mostly inhibitory effects, while stimulation of the somatosensory cortex provided mostly excitatory influences. The ratios of neurons generating primary excitatory and inhibitory responses to stimulation of the visual, auditory, and somatic cortices were 0.3:1, 0.6:1, and 3.2:1, respectively. More than 95% of the field-5 neurons were influenced from the primary sensory zones via di- and/or polysynaptic pathways. Monosynaptic excitatory inputs from the visual cortex were identified for 3.8% of interneurons and 6.9% of output PAZ neurons; for the auditory cortical inputs, the respective figures were 1.7 and 3.5%. Monosynaptic connections with the somatic cortex were found only for 4% of the interneurons under study. It has been concluded that interaction of heteromodal signals coming to the PAZ via the corticopetal and associative inputs occurs on neurons of all the cortical layers.     

Brief Subthreshold Events Can Act as Hebbian Signals for Long-Term Plasticity

Background

Action potentials are thought to be determinant for the induction of long-term synaptic plasticity, the cellular basis of learning and memory. However, neuronal activity does not lead systematically to an action potential but also, in many cases, to synaptic depolarizing subthreshold events. This is particularly exemplified in corticostriatal information processing. Indeed, the striatum integrates information from the whole cerebral cortex and, due to the membrane properties of striatal medium spiny neurons, cortical inputs do not systematically trigger an action potential but a wide range of subthreshold postsynaptic depolarizations. Accordingly, we have addressed the following question: does a brief subthreshold event act as a Hebbian signal and induce long-term synaptic efficacy changes?

Methodology/Principal Findings

Here, using perforated patch-clamp recordings on rat brain corticostriatal slices, we demonstrate, that brief (30 ms) subthreshold depolarizing events in quasi-coincidence with presynaptic activity can act as Hebbian signals and are sufficient to induce long-term synaptic plasticity at corticostriatal synapses. This “subthreshold-depolarization dependent plasticity” (SDDP) induces strong, significant and bidirectional long-term synaptic efficacy changes at a very high occurrence (81%) for time intervals between pre- and postsynaptic stimulations (Δt) of −110<Δt<+110 ms. Such subthreshold depolarizations are able to induce robust long-term depression (cannabinoid type-1 receptor-activation dependent) as well as long-term potentiation (NMDA receptor-activation dependent).

Conclusion/Significance

Our data show the existence of a robust, reliable and timing-dependent bidirectional long-term plasticity induced by brief subthreshold events paired with presynaptic activity. The existence of a subthreshold-depolarization dependent plasticity extends considerably, beyond the action potential, the neuron''s capabilities to express long-term synaptic efficacy changes.     

BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity

High levels of manganese (Mn) exposure decrease striatal medium spiny neuron (MSN) dendritic length and spine density, but the mechanism(s) are not known. The Huntingtin (HTT) gene has been functionally linked to cortical brain‐derived neurotrophic factor (BDNF) support of striatal MSNs via phosphorylation at serine 421. In Huntington's disease, pathogenic CAG repeat expansions of HTT decrease synthesis and disrupt transport of cortical–striatal BDNF, which may contribute to disease, and Mn is a putative environmental modifier of Huntington's disease pathology. Thus, we tested the hypothesis that changes in MSN dendritic morphology Mn due to exposure are associated with decreased BDNF levels and alterations in Htt protein. We report that BDNF levels are decreased in the striatum of Mn‐exposed non‐human primates and in the cerebral cortex and striatum of mice exposed to Mn. Furthermore, proBDNF and mature BDNF concentrations in primary cortical and hippocampal neuron cultures were decreased by exposure to Mn confirming the in vivo findings. Mn exposure decreased serine 421 phosphorylation of Htt in cortical and hippocampal neurons and increased total Htt levels. These data strongly support the hypothesis that Mn‐exposure‐related MSN pathology is associated with decreased BDNF trophic support via alterations in Htt.

     

A possible mechanism of dopamine-induced synergistic disinhibition of thalamic cells via "direct" and "indirect" pathways in basal ganglia

On the basis of the mechanism of synaptic plasticity that we have earlier suggested for striatal spiny neurons and with regard to the known data about the predominance of dopamine-sensitive D1/D2 receptors on the striatonigral/striatopallidal cells it is hypothesized that the induction of the long-term potentiation/depression of the efficacy of excitatory cortical inputs to these cells can underlie the excitatory/inhibitory effect of dopamine on the activity of neurons that originate the "direct"/"indirect" pathways through the basal ganglia. Both these effects will lead to an enhancement of the activity of thalamic cells and activity of the efferent neocortical neurons excited by thalamic cells. The long-term potentiation of corticostriatal inputs to striosomal neurons, where, predominantly, D1 receptors are located, can also be induced by dopamine. This effect can be responsible of a rise of inhibition of dopaminergic cells and decrease in dopamine release by these cells. Such an event sequence can provide a stable dopamine concentration in the loop neocortex-basal ganglia-thalamus-neocortex.     

Whole-Brain Mapping of Inputs to Projection Neurons and Cholinergic Interneurons in the Dorsal Striatum

The dorsal striatum integrates inputs from multiple brain areas to coordinate voluntary movements, associative plasticity, and reinforcement learning. Its projection neurons consist of the GABAergic medium spiny neurons (MSNs) that express dopamine receptor type 1 (D1) or dopamine receptor type 2 (D2). Cholinergic interneurons account for a small portion of striatal neuron populations, but they play important roles in striatal functions by synapsing onto the MSNs and other local interneurons. By combining the modified rabies virus with specific Cre- mouse lines, a recent study mapped the monosynaptic input patterns to MSNs. Because only a small number of extrastriatal neurons were labeled in the prior study, it is important to reexamine the input patterns of MSNs with higher labeling efficiency. Additionally, the whole-brain innervation pattern of cholinergic interneurons remains unknown. Using the rabies virus-based transsynaptic tracing method in this study, we comprehensively charted the brain areas that provide direct inputs to D1-MSNs, D2-MSNs, and cholinergic interneurons in the dorsal striatum. We found that both types of projection neurons and the cholinergic interneurons receive extensive inputs from discrete brain areas in the cortex, thalamus, amygdala, and other subcortical areas, several of which were not reported in the previous study. The MSNs and cholinergic interneurons share largely common inputs from areas outside the striatum. However, innervations within the dorsal striatum represent a significantly larger proportion of total inputs for cholinergic interneurons than for the MSNs. The comprehensive maps of direct inputs to striatal MSNs and cholinergic interneurons shall assist future functional dissection of the striatal circuits.     

3–Nitropropionic Acid–Induced Changes in Bilayer Fluidity in Synaptosomal Membranes: Implications for Huntington's Disease

The use of 3–nitropropionic acid (3–NP) and other mitochondria inhibitors to effectuate animal models of Huntington's disease has been well established. 3–NP administration has been shown to lead to pathology similar to that of HD, including massive loss of striatal neurons associated with oxidative stress. Oxidative stress induced by 3–NP also extends to the cortex, an area where little neuron loss occurs. No mechanism as of yet accounts for selective loss of striatal neurons while sparing cortical neurons. In the present study, a nitroxide stearate lipid bilayer-specific spin-label was utilized to probe 3–NP-induced fluidity changes in striatal and cortical synaptosomal membranes. In cortical synaptosomes, membrane fluidity increased in animals previously treated with 3–NP when compared to controls injected with saline vehicle, while in striatal synaptosomes, membrane fluidity decreased in animals treated with 3–NP when compared to controls. The results of the present study suggest that oxidatively-induced changes in membrane fluidity may be involved in mechanisms by which selective striatal neuronal loss occurs in this animal model of Huntington's disease.     

Frontal cortical afferents facilitate striatal nitric oxide transmission in vivo via a NMDA receptor and neuronal NOS-dependent mechanism

Striatal nitric oxide (NO) signaling plays a critical role in modulating neural processing and motor behavior. Nitrergic interneurons receive synaptic inputs from corticostriatal neurons and are activated via ionotropic glutamate receptor stimulation. However, the afferent regulation of NO signaling is poorly characterized. The role of frontal cortical afferents in regulating NO transmission was assessed in anesthetized rats using amperometric microsensor measurements of NO efflux and local field potential recordings. Low frequency (3 Hz) electrical stimulation of the ipsilateral cortex did not consistently evoke detectable changes in striatal NO efflux. In contrast, train stimulation (30 Hz) of frontal cortical afferents facilitated NO efflux in a stimulus intensity-dependent manner. Nitric oxide efflux evoked by train stimulation was transient, reproducible over time, and attenuated by systemic administration of either the NMDA receptor antagonist MK-801 or the neuronal NO synthase inhibitors 7-nitroindazole and NG-propyl-L-arginine. The interaction between NO efflux evoked via train stimulation and local striatal neuron activity was assessed using dual microsensor and local field potential recordings carried out concurrently in the contralateral and ipsilateral striatum, respectively. Systemic administration of the non-specific NO synthase inhibitor methylene blue attenuated both evoked NO efflux and the peak oscillation frequency (within the delta band) of local field potentials recorded immediately after train stimulation. Taken together, these observations indicate that feed-forward activation of neuronal NO signaling by phasic activation of frontal cortical afferents facilitates the synchronization of glutamate driven oscillations in striatal neurons. Thus, NO signaling may act to amplify coherent corticostriatal transmission and synchronize striatal output.     

Peering into the dendritic machinery of striatal medium spiny neurons

Striatal medium spiny neurons are principal players in the basal ganglia macrocircuits implicated in an astonishing array of psychomotor disorders, including Parkinson's disease, schizophrenia, Huntington's disease, and drug abuse. Using an elegant combination of 2-photon laser scanning microscopy and 2-photon uncaging of glutamate, Carter and Sabatini (this issue of Neuron) provide our first glimpse into the dendrites and spines of striatal medium spiny neurons. The results offer new insights into the workings of these clinically important yet mysterious neurons.     

UP States Protect Ongoing Cortical Activity from Thalamic Inputs

Cortical neurons in vitro and in vivo fluctuate spontaneously between two stable membrane potentials: a depolarized UP state and a hyperpolarized DOWN state. UP states temporally correspond with multineuronal firing sequences which may be important for information processing. To examine how thalamic inputs interact with ongoing cortical UP state activity, we used calcium imaging and targeted whole-cell recordings of activated neurons in thalamocortical slices of mouse somatosensory cortex. Whereas thalamic stimulation during DOWN states generated multineuronal, synchronized UP states, identical stimulation during UP states had no effect on the subthreshold membrane dynamics of the vast majority of cells or on ongoing multineuronal temporal patterns. Both thalamocortical and corticocortical PSPs were significantly reduced and neuronal input resistance was significantly decreased during cortical UP states – mechanistically consistent with UP state insensitivity. Our results demonstrate that cortical dynamics during UP states are insensitive to thalamic inputs.     

Spread of excitation in the upper layers (I–III) in an auditory cortex slab isolated from the cat

Research was performed on an auditory cortex slab isolated from unanesthetized immobilized cats after severing of the lower layers, preserving intact a bridge one, two, or three upper cortical layers under the pial membrane; the spike response of neurons on this slab to stimuli applied at the other side of this additional incision was observed. It was found that stimulation applied to level IV produces an excitatory wave which spreads to the upper cortical layers, leading to mono- and polysynaptic activation of neurons at all levels via the apical dendrite of pyramidal cells. Antidromic activation of layer IV neurons together with an especially high proportion of monosynaptic response was observed with the three upper cortical layers remaining intact. A possibly crucial role in the horizontal spread of excitation within the cerebral cortex of a major bundle of axons from cortical interneurons is discussed in this article.I. I. Mechnikov University, Odessa. Translated from Neirofiziologiya, Vol. 20, No. 4, July–August, 1988, pp. 546–553.     

Cerebral impedance with different kinds of anesthesia

Values of specific impedance of the cat's cerebral cortex were measured in the awake state and under various kinds of anesthesia (epontol, sodium thiopental, and ether). Measurements were taken at a frequency of 1 kHz using Ranck's four-electrode method. It was found that the development of general anesthesia was not accompanied by definite changes in impedance (±4%). The fact that substantial functional changes in cortical neurons such as these do not lead to changes in impedance can be explained by the relative independence of total cortical impedance from the membrane resistance of nerve cells. The quite small phase difference (5°) between the measuring current and the potential difference recorded in the cortex proves that the current passes virtually through the intercellular space only. The impedance of the cerebral cortex was assumed to be an entity essentially unrelated to the functional state of the cortex; the impedance cannot therefore determine the amplitude changes of the electrocorticogram (ECoG) recorded. The magnitude of cortical specific impedance was found to be 258 ±10·cm.A. V. Vishnevskii Institute of Surgery, Academy of Medical Sciences of the USSR. Moscow Physicotechnical Institute. Translated from Neirofiziologiya, Vol. 3, No. 3, pp. 260–265, May–June, 1971.     

Dynamics of a long-latency reflex pathway in the monkey

Angular wrist displacements in the monkey result in a short-latency (20–25 ms) reflex response of motor cortical cells in area 4 and separate peaks of activity in the gross EMG of the stretched muscles. Frequency domain analysis was carried out between (1) wrist position as input and motor cortical neuron response as output, (2) position as input and EMG response as output, and (3) motor cortical neuron response as input and EMG response as output. The results show that the dynamics of primary spindle afferents characterize the dynamics of the pathway to the motor cortex and that of the reflex loop. Results are discussed in terms of long-loop reflexes.     

The Possible Role of Spike Patterns in Cortical Information Processing

When the same visual stimulus is presented across many trials, neurons in the visual cortex receive stimulus-related synaptic inputs that are reproducible across trials (S) and inputs that are not (N). The variability of spike trains recorded in the visual cortex and their apparent lack of spike-to-spike correlations beyond that implied by firing rate fluctuations, has been taken as evidence for a low S/N ratio. A recent re-analysis of in vivo cortical data revealed evidence for spike-to-spike correlations in the form of spike patterns. We examine neural dynamics at a higher S/N in order to determine what possible role spike patterns could play in cortical information processing. In vivo-like spike patterns were obtained in model simulations. Superpositions of multiple sinusoidal driving currents were especially effective in producing stable long-lasting patterns. By applying current pulses that were either short and strong or long and weak, neurons could be made to switch from one pattern to another. Cortical neurons with similar stimulus preferences are located near each other, have similar biophysical properties and receive a large number of common synaptic inputs. Hence, recordings of a single neuron across multiple trials are usually interpreted as the response of an ensemble of these neurons during one trial. In the presence of distinct spike patterns across trials there is ambiguity in what would be the corresponding ensemble, it could consist of the same spike pattern for each neuron or a set of patterns across neurons. We found that the spiking response of a neuron receiving these ensemble inputs was determined by the spike-pattern composition, which, in turn, could be modulated dynamically as a means for cortical information processing.     

The potentiation of cortical neuron responses to noradrenaline by 2-phenylethylamine is independent of endogenous noradrenaline

2-Phenylethylamine (PE) is an endogenous brain amine which produces sympathomimetic responses and potentiates cortical neuron responses to noradrenaline (NA). In order to examine further the mechanism of action of PE, extracellular recordings were made of the activity of single neurones in the cerebral cortex in urethane-anesthetized rats. Sympathomimetic responses to PE were blocked by pretreatment with reserpine, reserpine plus -methyl-p-tyrosine and desipramine. It is concluded that the sympathomimetic responses to PE are indirect. 2-Phenylethylamine potentiated cortical neuron responses to electrical stimulation of the locus coeruleus in a dose-dependent manner. This was seen when PE was given systemically (with as little as 1 g/kg) and iontophoretically. The effects of PE were not reproduced by its metabolite phenylacetic acid or its putative metabolite phenylethanolamine. Iontophoretic applications of PE (0–6 nA, 2–5 minutes) potentiated cortical neuron responses to iontophoretically applied NA, without affecting the spontaneous firing rate, or the responses to iontophoretically applied GABA or acetylcholine. This effect of PE was not blocked by pretreatment with -methyl-p-tyrosine or desipramine, and was potentiated by pretreatment with reserpine and reserpine plus -methyl-p-tyrosine. It is probable that the ability of PE to modulate neuronal responses to NA does not involve the presynaptic NA terminal or endogenous NA and it is likely that PE acts directly to increase the efficacy of NA. These findings are consistent with the hypothesis that the physiological role of PE is to modulate catecholaminergic transmission within the central nervous system.     

Role of the basal ganglia in the occurrence of paradoxical sleep dreams (hypothetical mechanism)

A hypothetical mechanism of the basal ganglia involvement in the occurrence of paradoxical sleep dreams and rapid eye movements is proposed. According to this mechanism, paradoxical sleep is provided by facilitation of activation of cholinergic neurons in the pedunculopontine nucleus as a result of suppression of their inhibition from the output basal ganglia nuclei. This disinhibition is promoted by activation of dopaminergic cells by pedunculopontine neurons, subsequent rise in dopamine concentration in the input basal ganglia structure. striatum, and modulation of the efficacy of cortico-striatal inputs. In the absence of signals from retina, a disinhibition of neurons in the pedunculopontine nucleus and superior colliculus allows them to excite neurons in the lateral geniculate body and other thalamic nuclei projecting to the primary and higher visual cortical areas, prefrontal cortex and back into the striatum. Dreams as visual images and "motor hallucinations" are the result of an increase in activity of definitely selected groups of thalamic and neocortical neurons. This selection is caused by modifiable action of dopamine on long-term changes in the efficacy of synaptic transmission during circulation of signals in closed interconnected loops, each of which includes one of the visual cortical areas (motor cortex), one of the thalamic nuclei, limbic and one of the visual areas (motor area) of the basal ganglia. pedunculopontine nucleus, and superior colliculus. Simultaneous modification and modulation of synapses in diverse units of neuronal loops is provided by PGO waves. Disinhibition of superioir colliculus neurons and their excitation by pedunculopontine nucleus lead to an appearance of rapid eye movements during paradoxical sleep.     

Distribution of FMRFamide-like immunoreactive neurons in the central nervous system of the snail Helix pomatia

Summary The distribution of FMRFamide-like immunoreactive (FLI) neurons and their morphological characteristics have been investigated in the central nervous system of the snail, Helix pomatia L. Approximately phageal ganglion complex. More than 50% of the FLI neurons were located in the cerebral ganglia. The FLI neurons could be divided into four groups according to size: (i) giant neurons (over 100 m); (ii) large neurons (80–100 m); (iii) medium-sized neurons (40–70 m); (iv) small neurons (12–30 m). They were distributed i) in groups or clusters, typical of small neurons and ii) in solitary form or in groups comprising 2–3 cells, typical of large and giant neurons. Giant and large neurons revealed only limited arborizations in the neuropil, but rich branching towards and in the peripheral nerves. Some of the small neurons had extensive arborizations of varicose fibers in the neuropil. They may therefore play some role in integratory processes. Varicose FLI fibers were visualized in the cell body layer of the different ganglia, and in the neural sheath of both the ganglia and the peripheral nerves. We propose a multifunctional involvement of FLI neurons and FMRFamide-like neuropeptides in the Helix nervous system: (i) a synaptic or modulatory role in axo-axonic interactions in the neuropil; (ii) a direct influence on neuronal cell bodies in the cortical layer, (iii) innervation of different peripheral organs; and (iv) remote neurohormonal control of peripheral events through the neural sheath.