Cortical and thalamic excitation mediate the multiphasic responses of striatal cholinergic interneurons to motivationally salient stimuli.

Cholinergic interneurons are key components of striatal microcircuits. In primates, tonically active neurons (putative cholinergic interneurons) exhibit multiphasic responses to motivationally salient stimuli that mirror those of midbrain dopamine neurons and together these two systems mediate reward-related learning in basal ganglia circuits. Here, we addressed the potential contribution of cortical and thalamic excitatory inputs to the characteristic multiphasic responses of cholinergic interneurons in vivo. We first recorded and labeled individual cholinergic interneurons in anesthetized rats. Electron microscopic analyses of these labeled neurons demonstrated that an individual interneuron could form synapses with cortical and, more commonly, thalamic afferents. Single-pulse electrical stimulation of ipsilateral frontal cortex led to robust short-latency (<20 ms) interneuron spiking, indicating monosynaptic connectivity, but firing probability progressively decreased during high-frequency pulse trains. In contrast, single-pulse thalamic stimulation led to weak short-latency spiking, but firing probability increased during pulse trains. After initial excitation from cortex or thalamus, interneurons displayed a "pause" in firing, followed by a "rebound" increase in firing rate. Across all stimulation protocols, the number of spikes in the initial excitation correlated positively with pause duration and negatively with rebound magnitude. The magnitude of the initial excitation, therefore, partly determined the profile of later components of multiphasic responses. Upon examining the responses of tonically active neurons in behaving primates, we found that these correlations held true for unit responses to a reward-predicting stimulus, but not to the reward alone, delivered outside of any task. We conclude that excitatory inputs determine, at least in part, the multiphasic responses of cholinergic interneurons under specific behavioral conditions.

A new theory based on possible existence of timing control by intracellular photons in tonically active neurons.

Time perception in living organisms, especially mammals, and understanding the timing of their internal organs, have always been the topic of interest in neuroscience. In this study, our theory considers the photonic behavior on time control by some particular or some block of neurons. Photon emission by mitochondria has regular timing in intercellular process. In other words, due to the main mitochondrial function of cellular respiration as well as the source of photon emission, it is possible to deduce photon at a specific rate in TANs (Tonically Active Neurons). If photoreceptors exist in the neurons of the nervous system, photons can be received at a regulated time. Thereby, neurons can produce a constant-frequency signal for subsequent stimuli. Our studies conducted in the CNS (Central Nervous System) and TANs, and it seems that photoreceptors are present in TANs. Photons are interpreted by a series of neurons and produce an oscillating rhythm. These rhythms can be the basis of the body's chronological activity in different areas of the CNS. If this hypothesis is true, it can be deduced that an independent factor, excluding circadian activities, exists for living activities. Different neuronal structures will also be responsible for understanding the time. Although this hypothesis is far from a complete evaluation, it can compensate for some of the other problems. For instance, a series of inconsistencies that occur in some neurological diseases, such as Parkinson diseases can be well justified by this hypothesis.

Pauses in Striatal Cholinergic Interneurons: What is Revealed by Their Common Themes and Variations?

Striatal cholinergic interneurons, the so-called tonically active neurons (TANs), pause their firing in response to sensory cues and rewards during classical conditioning and instrumental tasks. The respective pause responses observed can demonstrate many commonalities, such as constant latency and duration, synchronous occurrence in a population of cells, and coincidence with phasic activities of midbrain dopamine neurons (DANs) that signal reward predictions and errors. Pauses can however also show divergent properties. Pause latencies and durations can differ in a given TAN between appetitive vs. aversive outcomes in classical conditioning, initial excitation can be present or absent, and a second pause can variably follow a rebound. Despite more than 20 years of study, the functions of these pause responses are still elusive. Our understanding of pause function is hindered by an incomplete understanding of how pauses are generated. In this mini-review article, we compare pause types, as well as current key hypotheses for inputs underlying pauses that include dopamine-induced inhibition through D2-receptors, a GABA input from ventral tegmental area, and a prolonged afterhyperpolarization induced by excitatory input from the cortex or from the thalamus. We review how each of these mechanisms alone explains some but not all aspects of pause responses. These mechanisms might need to operate in specific but variable sets of sequences to generate a full range of pause responses. Alternatively, these mechanisms might operate in conjunction with an underlying control mechanism within cholinergic interneurons which could potentially provide a framework to generate the common themes and variations seen amongst pause responses.