The striatum is the main structure of the basal ganglia. The striatum receives inputs from various cortical areas, and its subregions play distinct roles in motor and emotional functions. Recently, striatal maps based on corticostriatal connectivity and striosome-matrix compartmentalization were developed, and we were able to subdivide the striatum into seven subregions. Dopaminergic modulation of the excitability of medium spiny neurons is critical for striatal function. In this study, we investigated the functional properties of dopamine signaling in seven subregions of the striatum from male mice. By monitoring the phosphorylation of PKA substrates including DARPP-32 in mouse striatal slices, we identified two subregions with low D1 receptor signaling: the dorsolateral portion of the intermediate/rostral part (DL-IR) and the intermediate/caudal part (IC). Low D1 receptor signaling in the two subregions was maintained by phosphodiesterase 10A and muscarinic M4 receptors. In an animal model of 6-OHDA-indu...

Although composing two words into a complex representation (e.g., “coffee cake”) is conceptually different from forming associations between a pair of words (e.g., “coffee, cake”), the brain regions supporting semantic composition have also been implicated for associative encoding. Here, we adopted a two-word magnetoencephalography (MEG) paradigm which varies compositionality (“French/Korean cheese” vs. “France/Korea cheese”) and strength of association (“France/French cheese” vs. “Korea/Korean cheese”) between the two words. We collected MEG data while 42 English speakers (24 females) viewed the two words successively in the scanner, and we applied both univariate regression analyses and multivariate pattern classification to the source estimates of the two words. We show that the left anterior and middle temporal lobe (LATL; LMTL) are distinctively modulated by semantic composition and semantic association. Specifically, the LATL is mostly sensitive to high-association compositional phrases, while the LM...

The non-psychoactive phytocannabinoid cannabidiol (CBD) has been shown to have analgesic effects in animal studies but little is known about its mechanism of action. We examined effects of CBD on intrinsic excitability of primary pain-sensing neurons. Studying acutely-dissociated capsaicin-sensitive mouse DRG neurons at 37°C, we found that CBD effectively inhibited repetitive action potential firing, from 15-20 action potentials evoked by 1-s current injections in control to 1-3 action potentials with 2 μM CBD. Reduction of repetitive firing was accompanied by reduction of action potential height, widening of action potentials, reduction of the afterhyperpolarization, and increased propensity to enter depolarization block. Voltage clamp experiments showed that CBD inhibited both TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) sodium currents in a use-dependent manner. CBD showed strong state-dependent inhibition of TTX-R channels, with fast binding to inactivated channels during depolarizations and slow un...

The Russian fox-farm experiment is an unusually long-running and well-controlled study designed to replicate wolf-to-dog domestication. As such, it offers an unprecedented window onto the neural mechanisms governing the evolution of behavior. Here we report evolved changes to gray matter morphology resulting from selection for tameness vs. aggressive responses toward humans in a sample of 30 male fox brains. Contrasting with standing ideas on the effects of domestication on brain size, tame foxes did not show reduced brain volume. Rather, gray matter volume in both the tame and aggressive strains was increased relative to conventional farm foxes bred without deliberate selection on behavior. Furthermore, tame- and aggressive-enlarged regions overlapped substantially, including portions of motor, somatosensory, and prefrontal cortex, amygdala, hippocampus, and cerebellum. We also observed differential morphological covariation across distributed gray matter networks. In one prefrontal-cerebellum network, th...

The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathologic aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain ( n = 30, male and female). We find that tacrolimus reduces hippocampal ( p = 0.001) and parahippocampal ( p = 0.002) neurite density index, as well as protects against an age-associated increase in the parahippocampal ( p = 0.007) orientation dispersion index. Tacrolimus also protects against an age-related decrease in fractional anisotropy in the prefrontal cortex ( p < 0.0001). We also show that these microstructural alterations precede cognitive decline and gross atrophy. These results support the idea that calcineurin inhibitors may have the potential to prevent aging-related pathology if administere...

Forrest Gump or The Matrix ? Preference-based decisions are subjective and entail self-reflection. However, these self-related features are unaccounted for by known neural mechanisms of valuation and choice. Self-related processes have been linked to a basic interoceptive biological mechanism, the neural monitoring of heartbeats, in particular in ventromedial prefrontal cortex (vmPFC), a region also involved in value encoding. We thus hypothesized a functional coupling between the neural monitoring of heartbeats and the precision of value encoding in vmPFC. Human participants of both sexes were presented with pairs of movie titles. They indicated either which movie they preferred or performed a control objective visual discrimination that did not require self-reflection. Using magnetoencephalography, we measured heartbeat-evoked responses (HERs) before option presentation and confirmed that HERs in vmPFC were larger when preparing for the subjective, self-related task. We retrieved the expected cortical va...

Many older listeners have difficulty understanding speech in noise, when cues to speech-sound identity are less redundant. The amplitude envelope of speech fluctuates dramatically over time, and features such as the rate of amplitude change at onsets (attack) and offsets (decay), signal critical information about the identity of speech sounds. Aging is also thought to be accompanied by increases in cortical excitability, which may differentially alter sensitivity to envelope dynamics. Here, we recorded electroencephalography in younger and older human adults (of both sexes) to investigate how aging affects neural synchronization to 4 Hz amplitude-modulated noises with different envelope shapes (ramped: slow attack and sharp decay; damped: sharp attack and slow decay). We observed that subcortical responses did not differ between age groups, whereas older compared with younger adults exhibited larger cortical responses to sound onsets, consistent with an increase in auditory cortical excitability. Neural ac...

In humans, impaired response inhibition is characteristic of a wide range of psychiatric diseases and of normal aging. It is hypothesized that the right inferior frontal cortex (rIFC) plays a key role by inhibiting the motor cortex via the basal ganglia. The electroencephalography (EEG)-derived β-rhythm (15–29 Hz) is thought to reflect communication within this network, with increased right frontal β-power often observed before successful response inhibition. Recent literature suggests that averaging spectral power obscures the transient, burst-like nature of β-activity. There is evidence that the rate of β-bursts following a Stop signal is higher when a motor response is successfully inhibited. However, other characteristics of β-burst events, and their topographical properties, have not yet been examined. Here, we used a large human (male and female) EEG Stop Signal task (SST) dataset ( n = 218) to examine averaged normalized β-power, β-burst rate, and β-burst “volume” (which we defined as burst duration...

Some of us fortunate enough to have published a paper in The Journal of Neuroscience in its inaugural year (1981) have been asked to write a Progressions article addressing our views on the significance of the original work and how ideas about the topic of that work have evolved over the last 40 years. These questions cannot be effectively considered without placing them in the context of the incredible growth of the overall field of neuroscience over these last four decades. For openers, in 1981, the Nobel Prize was awarded to three neuroscience superstars: Roger Sperry, David Hubel, and Torsten Wiesel. Not a bad year to launch the Journal . With this as a backdrop, I divide this Progressions article into two parts. First, I discuss our original (1981) paper describing classical conditioning in Aplysia californica , and place our results in the context of the state of the field at the time. Second, I fast forward to the present and consider some of remarkable progress in the broad field of learning and me...