Two Basal Forebrain Cholinergic Neuron Types Show Distinct Properties

Post by Stephanie Williams

What's the science?

The basal forebrain contains many neurons that release a neurotransmitter called acetylcholine. Collectively, cholinergic (acetylcholine-releasing) neurons have been associated with many different broad cognitive processes, including arousal-regulation, memory, and attention. There is some previous evidence that cholinergic neurons are not a homogenous group, and that there may be subtypes of cholinergic neurons in the basal forebrain that are functionally distinct. This week in Nature Neuroscience, Laszlovszky and colleagues perform both in vivo and in vitro experiments to examine the heterogeneity of cholinergic neurons.

How did they do it?                             

The authors performed a series of electrophysiological and optogenetic experiments in mice performing behavioral tasks (“in vivo”) and in slices of brains that had been extracted from mice (“in vitro”). During the in vivo experiments, the authors recorded from the brains of awake and behaving mice using extracellular tetrodes. Cholinergic neurons were engineered to contain a photosensitive protein called channel rhodopsin that would respond to a particular light, which allowed them to be identified in the basal forebrain. The authors analyzed their recordings to characterize the firing properties of these cholinergic neurons in awake behaving mice. They also used the behavior of mice in conjunction with the in vivo electrophysiological recordings to investigate whether there were distinct subtypes of cholinergic basal forebrain neurons that were linked to behavioral outcomes. They analyzed the activity of cholinergic basal forebrain neurons after reward and punishment to understand if cholinergic neurons signalled information about reinforcements. The authors also recorded from 2 or 3 cholinergic neurons simultaneously to determine whether the cholinergic subtypes showed synchronous activity.  

During the in vitro experiments, the authors wanted to evaluate whether there were two distinct types of basal forebrain cholinergic neurons. They applied current to elicit spikes from cholinergic neurons in basal forebrain slices and measured these using whole-cell patch clamp recordings. The authors used recordings from auditory cortex and from basal forebrain to examine the relationship between basal forebrain cholinergic neurons and cortical activity. They confirmed that the cholinergic neurons were connected to cortical circuits by using a light to activate cholinergic neurons and looking for corresponding activity in cortical areas. They then examined whether the amount of synchrony between basal forebrain cholinergic neurons and auditory cortex was behaviorally significant during an auditory task.

What did they find?

The authors identified two types of cholinergic basal forebrain neurons that showed distinct firing patterns in vivo and in vitro: 1) burst-firing neurons and 2) rhythmic, non-bursting neurons in the posterior basal forebrain. The spiking activity of the burst neurons depended on their membrane potential and the strength of the input to the cell. Sometimes the burst-firing cells fired bursts of discrete action potentials (coined burst-BFCN-SBs), and other times they showed a pattern of spikes with irregular timing between the spikes (coined burst-BFCN-PLs). The bursts of these neurons usually occurred after either administering either water (reward) or an air-puff (punishment), suggesting that the bursting neurons may represent salient stimuli. When the authors compared the activity of cholinergic basal forebrain neurons to the activity of other non-cholinergic basal forebrain neurons, they found that only a small few were capable of the regular rhythmic pattern.

When the authors recorded activity from basal forebrain cholinergic neurons, they found that pairs of bursting basal forebrain neurons often showed synchronous firing (“zero-phase” synchrony). The authors also found that the bursting cholinergic neurons showed synchronization to cortical theta-band oscillations. On the other hand, regular rhythmic basal forebrain neurons did not show strong synchronization to the cortical oscillations, despite the intrinsic theta-rhythmic firing of the rhythmic basal forebrain neurons. They also found that the two subtypes of basal forebrain cholinergic neurons had distinct relationships with behaviour during an auditory task. The synchronization of the bursting neurons with activity in the auditory cortex during the auditory stimulus presentation could predict behavioral response timing (any type of response). Alternatively, the synchronization of regular rhythmic basal forebrain neurons with activity in the auditory cortex was strongest before successful behavior, and predicted correct responses on the auditory task. This finding suggests that the bursting basal forebrain cholinergic neurons may convey unspecific, fast and efficient information.  

What's the impact?

The authors provide clear in vivo and in vitro evidence that there are two basal forebrain cholinergic cell types. They reconcile previous seemingly contradictory evidence by identifying two functionally distinct types of basal forebrain cholinergic neurons, and by characterizing the properties of these two types of neurons.

Laszlovszky et al. Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types. Nature Neuroscience. (2020). Access the original scientific publication here.