Dissection of the long-range projections of specific neurons at the synaptic level in the whole mouse brain

Abstract

Through synaptic connections, long-range circuits transmit information among neurons and connect different brain regions to form functional motifs and execute specific functions. Tracing the synaptic distribution of specific neurons requires submicron-level resolution information. However, it is a great challenge to map the synaptic terminals completely because these fine structures span multiple regions, even in the whole brain. Here, we develop a pipeline including viral tracing, sample embedding, fluorescent micro-optical sectional tomography, and big data processing. We mapped the whole-brain distribution and architecture of long projections of the parvalbumin neurons in the basal forebrain at the synaptic level. These neurons send massive projections to multiple downstream regions with subregional preference. With three-dimensional reconstruction in the targeted areas, we found that synaptic degeneration was inconsistent with the accumulation of amyloid-β plaques but was preferred in memory-related circuits, such as hippocampal formation and thalamus, but not in most hypothalamic nuclei in 8-month-old mice with five familial Alzheimer’s disease mutations. Our pipeline provides a platform for generating a whole-brain atlas of cell-type-specific synaptic terminals in the physiological and pathological brain, which can provide an important resource for the study of the organizational logic of specific neural circuits and the circuitry changes in pathological conditions.

Parvalbumin-expressing basal forebrain neurons mediate learning from negative experience

“…The BF contains a substantial GABAergic population that is approximately five times larger than its cholinergic population according to stereological estimates in rodents 4,6 . This inhibitory population contains a significant long-range projecting neuron pool, many of which express parvalbumin 7,8,[35][36][37][38] .…”

“…These projections include target areas implicated in cognitive processing, including frontal cortices and hippocampus 8,10,38 . In concert, non-specific lesions of the basal forebrain typically resulted in more substantial cognitive impairment compared to selective cholinergic lesions [39][40][41][42] , suggesting a role for non-cholinergic BF neurons in associative learning 42,43 .…”

Gene therapy of adeno‐associated virus (AAV) vectors in preclinical models of ischemic stroke

“…This can also overcome the characteristic of AAV being difficult to deliver across synapses, whether in the anterograde or retrograde direction. In addition, this strategy combined with whole‐brain imaging and reconstruction equipment such as fluorescence micro‐optical sectioning tomography may be able to reconstruct the projection of individual neurons or the entire neural circuitry of the brain 127,128 . AAV, combined with chemical genetics technology, also provides a way to regulate neuronal activity.…”

“…This can also overcome the characteristic of AAV being difficult to deliver across synapses, whether in the anterograde or retrograde direction. In addition, this strategy combined with whole-brain imaging and reconstruction equipment such as fluorescence micro-optical sectioning tomography may be able to reconstruct the projection of individual neurons or the entire neural circuitry of the brain 127,128. AAV, combined with chemical genetics technology, also provides a way to regulate neuronal activity.In neuroscience research, the biological characteristics of various AAVs have been extensively studied, and the FDA has approved Luxturna for treating RPE65-related Leber congenital amaurosis and Zolgensma for treating spinal muscular atrophy 129,130.…”

Cross-scale tracing of nanoparticles and tumors at the single-cell level using the whole-lung atlas

“…The fluorescence MOST (fMOST) system is suitable for fluorescent samples with the possibility to realize the spatial distribution of particles in the lesion (0.325 μm by 0.325 μm by 2 μm) (26). MOST/fMOST system had been adopted to get high-resolution and cross-scale reconstruction of hippocampal blood vessels (27), high-precision panoramic view of amyloid-β plaques (28), whole-brain mapping of neural circuits (25), neuronal projection and junction maps (29)(30)(31)(32), visualization of hepatic vessels (33), whole-heart networks of myocardium (34), and deposition behaviors of inhalable particles in the whole lung (35). However, there are few reports on the application of MOST/fMOST to study the distribution of nanoparticles in tumors.…”