The aggregation of proteins is central to many aspects of daily life, including food processing, blood coagulation, eye cataract formation disease and prion-related neurodegenerative infections [1][2][3][4][5] . However, the physical mechanisms responsible for amyloidosis-the irreversible fibril formation of various proteins that is linked to disorders such as Alzheimer's, Creutzfeldt-Jakob and Huntington's diseases-have not yet been fully elucidated [6][7][8][9] . Here, we show that different stages of amyloid aggregation can be examined by performing a statistical polymer physics analysis of single-molecule atomic force microscopy images of heat-denatured b-lactoglobulin fibrils. The atomic force microscopy analysis, supported by theoretical arguments, reveals that the fibrils have a multistranded helical shape with twisted ribbon-like structures. Our results also indicate a possible general model for amyloid fibril assembly and illustrate the potential of this approach for investigating fibrillar systems.Protein self-assembly is a wide-ranging phenomenon and is of great importance in several areas of science. The reversible formation of fibrils from globular proteins is a phenomenon occurring naturally, in vivo, for proteins such as actin and tubulin 10,11 . Other well-known examples of protein fibrillation include the irreversible amyloid fibril formation of various proteins implicated in neurological disorders such as Alzheimer's, Creutzfeldt-Jakob or Huntington's diseases. Typically, these fibrils have long, unbranched, and often twisted structures that are a few nanometres in diameter 1,8 . However, many peptides and proteins, including many globular food proteins that are used as gelling agents, foaming agents or emulsifiers, can also form amyloid-like structures in vitro. Such structures can possess desirable mechanical properties and can be used to create useful textures and structures 12,13 .An example of a fibril formation of globular proteins is provided by the fine-stranded heat-set gels formed by heating solutions of various globular food proteins such as ovalbumin, bovine serum albumin 12 and b-lactoglobulin 13 . b-Lactoglobulin has been particularly well studied, because it represents both a relevant model system and a major whey protein of interest to the food industry [14][15][16][17][18][19][20][21][22] .Despite the fact that the individual parameters controlling the aggregation of globular proteins into amyloid fibrils have been well identified, the driving force for such an aggregation process still remains obscure. Studies devoted to the characterization of fibril structures based on light, neutrons and X-ray scattering methods, being bulk techniques, have only provided an average ensemble picture of the fibrils 23 . Single-molecule techniques such as atomic force microscopy (AFM) and transmission electron microscopy (TEM) have recently emerged to probe amyloid fibrils at the molecular level [24][25][26][27] . Nevertheless, so far, a fully comprehensive picture of the aggregation behaviour...

Activation of the mesolimbic dopamine system reinforces goal-directed behavior. With repetitive stimulation, for example by chronic drug abuse, the reinforcement may become compulsive and intake continues even when facing major negative consequences. Here we gave mice the opportunity for optogenetic dopamine neuron self-stimulation (oDASS) and observed that only a fraction of mice persevered if they had to endure an electric shock. Compulsive lever pressing was associated with an activity peak in orbitofrontal cortex (OFC) to striatum (DS) projection terminals. While

Dopamine (DA) neurons of the VTA track cues and rewards to generate a reward prediction error signal during Pavlovian conditioning. Here we explored how these neurons respond to a self-paced, operant task in freely moving mice. The animal could trigger a reward-predicting cue by remaining in a specific location of an operant box for a brief time before moving to a spout for reward collection. VTA DA neurons were identified using DAT-Cre male mice that carried an optrode with minimal impact on the behavioral task. In vivo single-unit recordings revealed transient fast spiking responses to the cue and reward in correct trials, while for incorrect ones the activity paused, reflecting positive and negative error signals of a reward prediction. In parallel, a majority of VTA DA neurons simultaneously encoded multiple actions (e.g., movement velocity, acceleration, distance to goal, and licking) in sustained slow firing modulation. Applying a GLM, we show that such multiplexed encoding of rewarding and motor variables by individual DA neurons was only apparent while the mouse was engaged in the task. Downstream targets may exploit such goal-directed multiplexing of VTA DA neurons to adjust actions to optimize the task's outcome.

Prevention of compulsive cocaine taking Over time, about 20% of chronic cocaine users lose control and become addicted. There are indications that the differential efficacy of the brain serotonin (5-HT) system may be involved in the vulnerability to drug addiction. However, the relevant circuits and underlying cellular processes remain elusive. Li et al . discovered a synaptic mechanism in mice that underlies the modulatory role of 5-HT in reducing the likelihood of transition to compulsion and eventually addiction (see the Perspective by Miyazaki and Miyazaki). Cocaine binds to 5-HT transporters to block 5-HT reuptake. The elevated extracellular 5-HT activates 5-HT 1B receptors and causes presynaptic depression of a projection from the orbitofrontal cortex to the dorsal striatum. These changes reduce the likelihood of inducing postsynaptic potentiation at these synapses, which ultimately drives compulsion. —PRS