Cell-type-specific representation of spatial context in the rat prefrontal cortex.

The ability to represent one's own position in relation to cues, goals, or threats is crucial to successful goal-directed behavior. Using optotagging in knock-in rats expressing Cre recombinase in parvalbumin (PV) neurons (PV-Cre rats), we demonstrate cell-type-specific encoding of spatial and movement variables in the medial prefrontal cortex (mPFC) during goal-directed reward seeking. Single neurons encoded the conjunction of the animal's spatial position and the run direction, referred to as the spatial context. The spatial context was most prominently represented by the inhibitory PV interneurons. Movement toward the reward was signified by increased local field potential (LFP) oscillations in the gamma band but this LFP signature was not related to the spatial information in the neuronal firing. The results highlight how spatial information is incorporated into cognitive operations in the mPFC. The presented PV-Cre line opens the door for expanded research approaches in rats.

The mouse prefrontal cortex: Unity in diversity.

The prefrontal cortex (PFC) is considered to constitute the highest stage of neural integration and to be devoted to representation and production of actions. Studies in primates have laid the foundation for theories regarding the principles of prefrontal function and provided mechanistic insights. The recent surge of studies of the PFC in mice holds promise for evolvement of present theories and development of novel concepts, particularly regarding principles shared across mammals. Here we review recent empirical work on the mouse PFC capitalizing on the experimental toolbox currently privileged to studies in this species. We conclude that this line of research has revealed cellular and structural distinctions of the PFC and neuronal activity with direct relevance to theories regarding the functions of the PFC. We foresee that data-rich mouse studies will be key to shed light on the general prefrontal architecture and mechanisms underlying cognitive aspects of organized actions.

Publisher Correction: A whole-brain atlas of monosynaptic input targeting four different cell types in the medial prefrontal cortex of the mouse.

The Supplementary Information is available in the online version of this Publisher Correction.

A whole-brain atlas of monosynaptic input targeting four different cell types in the medial prefrontal cortex of the mouse.

The local and long-range connectivity of cortical neurons are considered instrumental to the functional repertoire of the cortical region in which they reside. In cortical networks, distinct cell types build local circuit structures enabling computational operations. Computations in the medial prefrontal cortex (mPFC) are thought to be central to cognitive operation, including decision-making and memory. We used a retrograde trans-synaptic rabies virus system to generate brain-wide maps of the input to excitatory neurons as well as three inhibitory interneuron subtypes in the mPFC. On the global scale the input patterns were found to be mainly cell type independent, with quantitative differences in key brain regions, including the basal forebrain. Mapping of the local mPFC network revealed high connectivity between the different subtypes of interneurons. The connectivity mapping gives insight into the information that the mPFC processes and the structural architecture underlying the mPFC's unique functions.

Prefrontal Parvalbumin Neurons in Control of Attention.

While signatures of attention have been extensively studied in sensory systems, the neural sources and computations responsible for top-down control of attention are largely unknown. Using chronic recordings in mice, we found that fast-spiking parvalbumin (FS-PV) interneurons in medial prefrontal cortex (mPFC) uniformly show increased and sustained firing during goal-driven attentional processing, correlating to the level of attention. Elevated activity of FS-PV neurons on the timescale of seconds predicted successful execution of behavior. Successful allocation of attention was characterized by strong synchronization of FS-PV neurons, increased gamma oscillations, and phase locking of pyramidal firing. Phase-locked pyramidal neurons showed gamma-phase-dependent rate modulation during successful attentional processing. Optogenetic silencing of FS-PV neurons deteriorated attentional processing, while optogenetic synchronization of FS-PV neurons at gamma frequencies had pro-cognitive effects and improved goal-directed behavior. FS-PV neurons thus act as a functional unit coordinating the activity in the local mPFC circuit during goal-driven attentional processing.

Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity.

The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near -65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ∼ 15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor-based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure-function relationships of the light-gated pore.

Pre-vaccination prevalence of human papillomavirus types in the genital tract of 15-23-year-old women attending a youth health clinic in Stockholm, Sweden.

Knowledge of the prevalence of different human papillomavirus (HPV) types in young girls is important for the early detection of changes in HPV prevalence, e.g. due to HPV vaccines. The purpose of this study was to obtain information on the prevalence of 24 different genital HPV types in a group of sexually active young women (aged 15-23 y) attending a major youth healthcare centre in Stockholm, before the introduction of public HPV vaccination of young women in the autumn of 2010. A total of 615 women were analyzed for 24 different, mainly high-risk HPV (HR-HPV) types using multiplex polymerase chain reaction and Luminex technology. A high HPV prevalence in this cohort was demonstrated, particularly with regard to HPV16, but also to all included HR-HPV types. Of the 544 successfully analyzed samples from non-vaccinated individuals, 70% were positive for the HPV types assayed for, and 62% were positive for HR-HPV types. Over a third (34.7%) of the women were infected with HPV16, and a high frequency of infections with HR-HPV types 51 (10.7%), 18 (10.1%), 52 (9.9%) and 73 (9.4%) was also observed. At least 9 different non-vaccine HR-HPV types were present with a prevalence of >6% in this selected group of young women.

Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?

In the county of Stockholm, between 1970 and 2002, we have previously reported a 3-fold parallel increase in the incidence of tonsillar squamous cell carcinoma (SCC) and the proportion of human papillomavirus (HPV) positive tonsillar SCC. Here, we have followed the above parameters in all patients (n = 120) diagnosed with tonsillar SCC during 2003-2007 in the same area, and also in correlation to our previous data. Ninety-eight pretreatment biopsies were available and presence of HPV DNA and HPV-16 E6 and E7 RNA were tested by polymerase chain reaction (PCR) and RT-PCR. Incidence data were obtained from the Swedish Cancer Registry. Data reported from 1970 to 2002 were also obtained for comparison. HPV DNA was present in 83 of 98 (85%) of the tonsillar SCC biopsies from 2003 to 2007 and 77 of these were HPV-16 positive. HPV-16 E6 and E7 RNA were found in 98% of 52 analyzed HPV-16 positive cases. The proportion of HPV-positive cancers had significantly increased both from 1970 to 2007 (p < 0.0001) as well from 2000 to 2007 (p < 0.01), with 68% (95% confidence interval (CI), 53-81) 2000-2002; 77% (95% CI, 63-87) 2003-2005; and 93% (95% CI, 82-99) 2006-2007. The incidence rate of HPV-positive tumors almost doubled each decade between 1970 and 2007, in parallel with a decline of HPV-negative tumors. In conclusion, the incidence of HPV-positive cancers is still increasing in the County of Stockholm, suggesting an epidemic of a virus-induced carcinoma, with soon practically all tonsillar SCC being HPV positive, as in cervical cancer.