The microbial community dynamics of cocaine sensitization in two behaviorally divergent strains of collaborative cross mice.

The gut-brain axis is increasingly recognized as an important pathway involved in cocaine use disorder. Microbial products of the murine gut have been shown to affect striatal gene expression, and depletion of the microbiome by antibiotic treatment alters cocaine-induced behavioral sensitization in C57BL/6J male mice. Some reports suggest that cocaine-induced behavioral sensitization is correlated with drug self-administration behavior in mice. Here, we profile the composition of the naïve microbiome and its response to cocaine sensitization in two collaborative cross (CC) strains. These strains display extremely divergent behavioral responses to cocaine sensitization. A high-responding strain, CC004/TauUncJ (CC04), has a gut microbiome that contains a greater amount of Lactobacillus than the cocaine-nonresponsive strain CC041/TauUncJ (CC41). The gut microbiome of CC41 is characterized by an abundance of Eisenbergella, Robinsonella and Ruminococcus. In response to cocaine, CC04 has an increased Barnsiella population, while the gut microbiome of CC41 displays no significant changes. PICRUSt functional analysis of the functional potential of the gut microbiome in CC04 shows a significant number of potential gut-brain modules altered after exposure to cocaine, specifically those encoding for tryptophan synthesis, glutamine metabolism, and menaquinone synthesis (vitamin K2). Depletion of the microbiome by antibiotic treatment revealed an altered cocaine-sensitization response following antibiotics in female CC04 mice. Depleting the microbiome by antibiotic treatment in males revealed increased infusions for CC04 during a cocaine intravenous self-administration dose-response curve. Together these data suggest that genetic differences in cocaine-related behaviors may involve the microbiome.

Songbirds can learn flexible contextual control over syllable sequencing.

The flexible control of sequential behavior is a fundamental aspect of speech, enabling endless reordering of a limited set of learned vocal elements (syllables or words). Songbirds are phylogenetically distant from humans but share both the capacity for vocal learning and neural circuitry for vocal control that includes direct pallial-brainstem projections. Based on these similarities, we hypothesized that songbirds might likewise be able to learn flexible, moment-by-moment control over vocalizations. Here, we demonstrate that Bengalese finches (Lonchura striata domestica), which sing variable syllable sequences, can learn to rapidly modify the probability of specific sequences (e.g. 'ab-c' versus 'ab-d') in response to arbitrary visual cues. Moreover, once learned, this modulation of sequencing occurs immediately following changes in contextual cues and persists without external reinforcement. Our findings reveal a capacity in songbirds for learned contextual control over syllable sequencing that parallels human cognitive control over syllable sequencing in speech.

Human speech and birdsong share numerous parallels. Both humans and birds learn their vocalizations during critical phases early in life, and both learn by imitating adults. Moreover, both humans and songbirds possess specific circuits in the brain that connect the forebrain to midbrain vocal centers. Humans can flexibly control what they say and how by reordering a fixed set of syllables into endless combinations, an ability critical to human speech and language. Birdsongs also vary depending on their context, and melodies to seduce a mate will be different from aggressive songs to warn other males to stay away. However, so far it was unclear whether songbirds are also capable of modifying songs independent of social or other naturally relevant contexts. To test whether birds can control their songs in a purposeful way, Veit et al. trained adult male Bengalese finches to change the sequence of their songs in response to random colored lights that had no natural meaning to the birds. A specific computer program was used to detect different variations on a theme that the bird naturally produced (for example, "ab-c" versus "ab-d"), and rewarded birds for singing one sequence when the light was yellow, and the other when it was green. Gradually, the finches learned to modify their songs and were able to switch between the appropriate sequences as soon as the light cues changed. This ability persisted for days, even without any further training. This suggests that songbirds can learn to flexibly and purposefully modify the way in which they sequence the notes in their songs, in a manner that parallels how humans control syllable sequencing in speech. Moreover, birds can learn to do this 'on command' in response to an arbitrarily chosen signal, even if it is not something that would impact their song in nature. Songbirds are an important model to study brain circuits involved in vocal learning. They are one of the few animals that, like humans, learn their vocalizations by imitating conspecifics. The finding that they can also flexibly control vocalizations may help shed light on the interactions between cognitive processing and sophisticated vocal learning abilities.