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The hemibrain connectome (Scheffer et al., 2020) provides large scale connectivity and morphology information for the majority of the central brain of Drosophila melanogaster. Using this data set, we provide a complete description of the most complex olfactory system studied at synaptic resolution to date, covering all first, second and third-order neurons of the olfactory system associated with the antennal lobe and lateral horn (mushroom body neurons are described in a parallel paper, Li et al., 2020). We develop a generally applicable strategy to extract information flow and layered organisation from synaptic resolution connectome graphs, mapping olfactory input to descending interneurons. This identifies a range of motifs including highly lateralised circuits in the antennal lobe and patterns of convergence downstream of the mushroom body and lateral horn. We also leverage a second data set (FAFB, Zheng et al., 2018) to provide a first quantitative assessment of inter- versus intra-individual stereotypy. Complete reconstruction of select developmental lineages in two brains (three brain hemispheres) reveals striking similarity in neuronal morphology across brains for >170 cell types. Within and across brains, connectivity correlates with morphology. Notably, neurons of the same morphological type show similar connection variability within one brain as across brains; this property should enable a rigorous quantitative approach to cell typing.

A central debate in the systems neuroscience of memory concerns whether different medial temporal lobe (MTL) structures support different processes in recognition memory. Using two recognition memory paradigms, we tested a rare patient (MH) with a perirhinal lesion that appeared to spare the hippocampus. Consistent with a similar previous case, MH showed impaired familiarity and preserved recollection. When compared with patients with hippocampal lesions appearing to spare perirhinal cortex, MH showed greater impairment on familiarity and less on recollection. Nevertheless, the hippocampal patients also showed impaired familiarity compared with healthy controls. However, when replacing this traditional categorization of patients with analyses relating memory performance to continuous measures of damage across patients, hippocampal volume uniquely predicted recollection, whereas parahippocampal, rather than perirhinal, volume uniquely predicted familiarity. We consider whether the familiarity impairment in MH and our patients with hippocampal lesions arises from “subthreshold” damage to parahippocampal cortex (PHC). Our data provide the most compelling neuropsychological support yet for dual-process models of recognition memory, whereby recollection and familiarity depend on different MTL structures, and may support a role for PHC in familiarity. Our study highlights the value of supplementing single-case studies with examinations of continuous brain–behavior relationships across larger patient groups.

A central debate in the systems neuroscience of memory concerns whether different medial temporal lobe (MTL) structures support different processes or material-types in recognition memory. We tested a rare patient (Patient MH) with a perirhinal lesion that appeared to spare the hippocampus, using two recognition memory paradigms, each run separately with faces, scenes and words. Replicating reports of a previous case, Patient MH showed impaired familiarity and preserved recollection, relative to controls, with no evidence for any effect of material-type. Moreover, when compared with other amnesic patients, who had hippocampal lesions that appeared to spare the perirhinal cortex, Patient MH showed greater impairment on familiarity and less on recollection, forming a double dissociation. However, when replacing this traditional, binary categorization of patients with a parametric analysis that related memory performance to continuous measures of brain damage across all patients, we found a different pattern: while hippocampal damage predicted recollection, it was parahippocampal instead of perirhinal (or entorhinal) cortex volume that predicted familiarity. Furthermore, there was no evidence that these brain-behavior relationships were moderated by material-type, nor by laterality of damage. Thus, while our data provide the most compelling support yet for dual-process models of recognition memory, in which recollection and familiarity depend on different MTL structures, they suggest that familiarity depends more strongly upon the parahippocampal rather than perirhinal cortex. More generally, our study reinforces the need to go beyond single-case and group studies, and instead examine continuous brain-behavior relationships across larger patient groups.

Summary Nervous systems contain sensory neurons, local neurons, projection neurons, and motor neurons. To understand how these building blocks form whole circuits, we must distil these broad classes into neuronal cell types and describe their network connectivity. Using an electron micrograph dataset for an entire Drosophila melanogaster brain, we reconstruct the first complete inventory of olfactory projections connecting the antennal lobe, the insect analog of the mammalian olfactory bulb, to higher-order brain regions in an adult animal brain. We then connect this inventory to extant data in the literature, providing synaptic-resolution “holotypes” both for heavily investigated and previously unknown cell types. Projection neurons are approximately twice as numerous as reported by light level studies; cell types are stereotyped, but not identical, in cell and synapse numbers between brain hemispheres. The lateral horn, the insect analog of the mammalian cortical amygdala, is the main target for this olfactory information and has been shown to guide innate behavior. Here, we find new connectivity motifs, including axo-axonic connectivity between projection neurons, feedback, and lateral inhibition of these axons by a large population of neurons, and the convergence of different inputs, including non-olfactory inputs and memory-related feedback onto third-order olfactory neurons. These features are less prominent in the mushroom body calyx, the insect analog of the mammalian piriform cortex and a center for associative memory. Our work provides a complete neuroanatomical platform for future studies of the adult Drosophila olfactory system., Graphical Abstract, Highlights • First complete parts list for second-order neurons of an adult olfactory system • Quantification of left-right stereotypy in cell and synapse number • Axo-axonic connections form hierarchical communities in the lateral horn • Local and memory-related feedback target projection neuron axons, Bates, Schlegel et al. report the first complete part list of second-order neurons in an adult arthropod olfactory system. They show that these neurons are stereotyped across hemispheres and reveal their hierarchical interconnectivity and how they connect to third-order targets and memory-related neurons.

Nervous systems contain sensory neurons, local neurons, projection neurons and motor neurons. To understand how these building blocks form whole circuits, we must distil these broad classes into neuronal cell types and describe their network connectivity. Using an electron micrograph dataset for an entireDrosophila melanogasterbrain, we reconstruct the first complete inventory of olfactory projections connecting the antennal lobe, the insect analogue of the mammalian olfactory bulb, to higher-order brain regions in an adult animal brain. We then connect this inventory to extant data in the literature, providing synaptic-resolution ‘holotypes’ both for heavily investigated and previously unknown cell types. Projection neurons are approximately twice as numerous as reported by light level studies; cell types are stereotyped, but not identical, in cell and synapse numbers between brain hemispheres. The lateral horn, the insect analogue of the mammalian cortical amygdala, is the main target for this olfactory information and has been shown to guide innate behaviour. Here, we find new connectivity motifs, including: axo-axonic connectivity between projection neurons; feedback and lateral inhibition of these axons by local neurons; and the convergence of different inputs, including non-olfactory inputs and memory-related feedback onto lateral horn neurons. This differs from the configuration of the second most prominent target for olfactory projection neurons: the mushroom body calyx, the insect analogue of the mammalian piriform cortex and a centre for associative memory. Our work provides a complete neuroanatomical platform for future studies of the adultDrosophilaolfactory system.HighlightsFirst complete parts list for second-order neurons of an adult olfactory systemQuantification of left-right stereotypy in cell and synapse numberAxo-axonic connections form hierarchical communities in the lateral hornLocal neurons and memory-related feedback target projection neuron axons