Across three experiments, PET scans were obtained while subjects performed different word-stem completion and FIXATION control tasks designed to study the functional anatomy of memory retrieval. During each of three different word-stem completion scans, word-stem cues were visually presented in uppercase letters. The RECALL task required explicit retrieval of study words presented prior to the PET scan. The PRIMING task addressed the implicit effects of the prior study words without requiring intentional recall. The BASELINE task encouraged retrieval of information from a general knowledge store. Across experiments, the similarity between study words and word stems was manipulated by presenting prescan study words in either uppercase letters identical to the stems, in lowercase letters, or auditorily. The PRIMING task was not studied with auditory presentation. Many activations were consistent across experiments. The BASELINE task activated several regions in response to the reading and verbal- response demands of the task (visual, motor, and premotor cortices, cerebellum), as well as a left prefrontal region. The RECALL task additionally activated regions in anterior right prefrontal cortex. Bilateral occipitotemporal regions showed blood flow reductions during the PRIMING task as compared to the BASELINE task. Activation in the right hippocampal/parahippocampal region was observed only in one experiment, and no experiment showed activation in the left medial temporal lobe. These experiments suggest that areas of frontal cortex play a role in explicit recall and that an effect of priming may be to require less activation of perceptual regions for the processing of recently presented information.

In the neocortex, subcerebral axonal projections originate largely from layer 5 (L5) extratelencephalic-projecting (ET) neurons. The highly distinctive morpho-electric properties of these neurons have mainly been described in rodents, where ET neurons can be labeled by retrograde tracers or transgenic lines. Similar labeling strategies are not possible in the human neocortex, rendering the translational relevance of findings in rodents unclear. We leveraged the recent discovery of a transcriptomically-defined L5 ET neuron type to study the properties of human L5 ET neurons in neocortical brain slices derived from neurosurgeries. Patch-seq recordings, where transcriptome, physiology and morphology are assayed from the same cell, revealed many conserved morpho-electric properties of human and rodent L5 ET neurons. Divergent properties were also apparent but were often smaller than differences between cell types within these two species. These data suggest a conserved function of L5 ET neurons in the neocortical hierarchy, but also highlight marked phenotypic divergence possibly related to functional specialization of human neocortex.

24Gene expression studies suggest that differential ion channel expression 25 contributes to differences in rodent versus human neuronal physiology. We 26 tested whether h-channels more prominently contribute to the physiological 27 properties of human compared to mouse supragranular pyramidal neurons. 28Single cell/nucleus RNA sequencing revealed ubiquitous HCN1-subunit 29 expression in excitatory neurons in human, but not mouse supragranular layers. 30Using patch-clamp recordings, we found stronger h-channel-related membrane 31properties in supragranular pyramidal neurons in human temporal cortex, 32 compared to mouse supragranular pyramidal neurons in temporal association 33 area. The magnitude of these differences depended upon cortical depth and was 34 largest in pyramidal neurons in deep L3. Additionally, pharmacologically blocking 35 h-channels produced a larger change in membrane properties in human 36 compared to mouse neurons. Finally, using biophysical modeling, we provided 37 evidence that h-channels promote the transfer of theta frequencies from dendrite-38 to-soma in human L3 pyramidal neurons. Thus, h-channels contribute to 39 between-species differences in a fundamental neuronal property. 40 41 integration of synaptic input that is most pronounced in deep L3 pyramidal 88 neurons of human temporal cortex, which may generally represent an important 89 evolutionary adaptation for very large pyramidal neurons in the human neocortex. 90 Experimental Procedures 91Human surgical specimens 92Surgical specimens were obtained from local hospitals (Harborview Medical 94 in collaboration with local neurosurgeons. All patients provided informed consent 95 and experimental procedures were approved by hospital institute review boards 96 before commencing the study. The bulk of data included in this study were 97 obtained from tissue from 10 patients with temporal lobe epilepsy with a mean 98 age of 38.10 ± 15.67. Four patients were male and 6 were female. Additionally, 99 data were obtained from tissue from one patient who had undergone deep tumor 100 resection from the temporal lobe. Tissue obtained from surgery was distal to the 101 core pathological tissue and was deemed not to be of diagnostic value. 102Specimens were placed in a sterile container filled with an artificial cerebral 103 spinal fluid (aCSF) composed of (in mM): 92 with N-methyl-D-glucamine 104 (NMDG), 2.5 KCl, 1.25 NaH 2 PO 4 , 30 NaHCO 3 , 20 4-(2-hydroxyethyl)-1-105 piperazineethanesulfonic acid (HEPES), 25 glucose, 2 thiourea, 5 Na-ascorbate, 1063 Na-pyruvate, 0.5 CaCl 2 ·4H 2 O and 10 MgSO 4 ·7H 2 O. The pH of the NMDG 107 aCSF was titrated to pH 7.3-7.4 with concentrated hydrochloric acid and the 108 osmolality was 300-305 mOsmoles/Kg. The solution was pre-chilled to 2-4°C 109 and thoroughly bubbled with carbogen (95% O 2 /5% CO 2 ) prior to collection. 110 Surgical specimens were quickly transported from the surgical site to the 111 laboratory while continuously bubbled with carbogen (transportation time: 10-40 112 minutes). 113 Acute br...