Memory guidance of value-based decision making at an abstract level of representation.

Value-based decisions about alternatives we have never experienced can be guided by associations between current choice options and memories of prior reward. A critical question is how similar memories need to be to the current situation to effectively guide decisions. We address this question in the context of associative learning of faces using a sensory preconditioning paradigm. We find that memories of reward spread along established associations between faces to guide decision making. While memory guidance is specific for associated facial identities, it does not only occur for the specific images that were originally encountered. Instead, memory guidance generalizes across different images of the associated identities. This suggests that memory guidance does not rely on a pictorial format of representation but on a higher, view-invariant level of abstraction. Thus, memory guidance operates on a level of representation that neither over- nor underspecifies associative relationships in the context of obtaining reward.

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACNA1H encoding for Cav3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Cav3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominant-negative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Cav3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Cav3.2 channel function. These findings add to the notion that loss-of-function of Cav3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.