BMC Neuroscience 

Abstract: We have collected a comprehensive set of multi-unit data on dissociated cortical cultures. Previous studies of the development of the electrical activity of dissociated cultures of cortical neurons each focused on limited aspects of its dynamics, and were often based on small numbers of observed cultures. We followed 58 cultures of different densities – 3000 to 50,000 neurons on areas of 30 to 75 mm2 – growing on multi-electrode arrays (MEAs) during the first five weeks of their development. Plating density had a profound effect on development. While the aggregate spike detection rate scaled linearly with density, as expected from the number of cells in proximity to electrodes, dense cultures started to exhibit bursting behavior earlier in development than sparser cultures. Analysis of responses to electrical stimulation suggests that axonal outgrowth likewise occurred faster in dense cultures. After two weeks, the network activity was dominated by population bursts in most cultures. In contrast to previous reports, development continued with changing burst patterns throughout the observation period. Burst patterns were extremely varied, with inter-burst intervals between 1 and 300 s, different amounts of temporal clustering of bursts, and different firing rate profiles during bursts. During certain stages of development bursts were organized into tight clusters with highly conserved internal structure. Dissociated cultures of cortical cells exhibited a much richer repertoire of activity patterns than previously reported. Except for the very sparsest cultures, all cultures exhibited globally synchronized bursts, but bursting patterns changed over the course of development, and varied considerably between preparations. This emphasizes the importance of using multiple preparations – not just multiple cultures from one preparation – in any study involving neuronal cultures. These results are based on 963 half-hour-long recordings. To encourage further investigation of the rich range of behaviors exhibited by cortical cells in vitro, we are making the data available to other researchers, together with Matlab code to facilitate access.

Abstract: Learning the associations between cues and rewards (classical or Pavlovian conditioning) or between cues, actions, and rewards (instrumental or operant conditioning) involves reinforcement of neuronal activity by rewards or punishments. Typically, the reward comes seconds after reward-predicting cues or reward-triggering actions, creating an explanatory conundrum known in the behavioral literature as the distal reward problem and in the reinforcement learning literature as the credit assignment problem. Indeed, how does the animal know which of the many cues and actions preceding the reward should be credited for the reward? In neural terms, in which sensory cues and motor actions correspond to neuronal firings, how does the brain know what firing patterns, out of an unlimited repertoire of all possible patterns, are responsible for the reward if the patterns are no longer there when the reward arrives? How does it know which spikes of which neurons result in the reward if many neurons fire during the waiting period to the reward? Finally, how does the common reinforcement signal in the form of the neuromodulator dopamine (DA) influence the right synapses at the right time, if DA is released globally to many synapses? Here, I show how the credit assignment problem could be solved in a network of cortical spiking neurons with DA-modulated plasticity. The model is based on the experimental findings that DA modulates synaptic plasticity by enhancing long-term potentiation (LTP) and long-term depression (LTD): For example, in hippocampus, dopamine D1 receptor agonists enhance tetanus-induced LTP, but the effect disappears if the agonist arrives at the synapses 15–25 seconds after the tetanus, thereby suggesting the existence of a short window of opportunity for the enhancement. My major hypothesis is that DA acts the same way on the spike-timing dependent synaptic plasticity (STDP). That is, a particular order of firing induces a synaptic change (positive or negative), which is enhanced if extracellular DA is present during the critical window of a few seconds. I show that DA modulation of STDP has a built-in property of instrumental conditioning: It can reinforce firing patterns occurring on a millisecond time scale even when they are followed by rewards that are delayed by seconds. This property relies on the existence of slow synaptic processes that act as "synaptic eligibility traces" or "synaptic tags". These processes are triggered by nearly-coincident spiking patterns, but due to a short temporal window of STDP, they are not affected by random firing during the waiting period to the reward. This "insensitivity" of the synaptic tags to the random ongoing activity during the waiting period is the key feature that distinguishes my approach from previous studies, which require that the network be quiet during the waiting period or that the patterns are preserved as a sustained response. I also discuss why this mechanism works only when precise firing patterns are embedded into the sea of noise and why it fails in the mean firing rate models. I also present a spiking network implementation of the most important aspect of the temporal difference (TD) reinforcement learning rule – the shift of reward-triggered release of DA from unconditional stimuli to reward-predicting conditional stimuli. This study emphasizes the importance of precise firing patterns in brain dynamics and suggests how a global diffusive reinforcement signal in the form of DA can selectively influence the right synapses at the right time. The model provides a testable prediction on the action of DA on STDP, which will be tested by G. Bi (Pittsburgh University) and R. Froemke (UCSF) (personal communications).

Abstract: Lesion studies in human and non-human primates have linked several different regions of prefrontal cortex (PFC) with the ability to inhibit inappropriate motor responses. However, recent functional neuroimaging studies have specifically implicated right inferior PFC in response inhibition. Right frontal dominance for inhibitory motor control has become a commonly accepted view, although support for this position has not been consistent. Particularly conspicuous is the lack of data on the importance of the homologous region in the left hemisphere. To investigate whether the left inferior frontal gyrus (IFG) is critical for response inhibition, we used neuropsychological methodology with carefully characterized brain lesions in neurological patients. Twelve individuals with damage in the left IFG and the insula were tested in a Go/NoGo response inhibition task. In alternating blocks, the difficulty of response inhibition was easy (50% NoGo trials) or hard (10% NoGo trials). Controls showed the predicted pattern of faster reaction times and more false alarm errors in the hard condition. Left IFG patients had higher error rates than controls in both conditions, but were more impaired in the hard condition, when a greater degree of inhibitory control was required. In contrast, a patient control group with orbitofrontal cortex lesions showed intact performance. Recent neuroimaging studies have focused on a highly specific association between right IFG and inhibitory control. The present results indicate that the integrity of left IFG is also critical for successful implementation of inhibitory control over motor responses. Our findings demonstrate the importance of obtaining converging evidence from multiple methodologies in cognitive neuroscience.

Abstract: Intranasal delivery provides a practical, non-invasive method of bypassing the blood-brain barrier (BBB) to deliver therapeutic agents to the brain and spinal cord. This technology allows drugs that do not cross the BBB to be delivered to the central nervous system within minutes. It also directly delivers drugs that do cross the BBB to the brain, eliminating the need for systemic administration and its potential side effects. This is possible because of the unique connections that the olfactory and trigeminal nerves provide between the brain and external environment. Intranasal delivery does not necessarily require any modification to therapeutic agents. A wide variety of therapeutics, including both small molecules and macromolecules, can be targeted to the olfactory system and connected memory areas affected by Alzheimer's disease. Using the intranasal delivery system, researchers have reversed neurodegeneration and rescued memory in a transgenic mouse model of Alzheimer's disease. Intranasal insulin-like growth factor-I, deferoxamine, and erythropoietin have been shown to protect the brain against stroke in animal models. Intranasal delivery has been used to target the neuroprotective peptide NAP to the brain to treat neurodegeneration. Intranasal fibroblast growth factor-2 and epidermal growth factor have been shown to stimulate neurogenesis in adult animals. Intranasal insulin improves memory, attention, and functioning in patients with Alzheimer's disease or mild cognitive impairment, and even improves memory and mood in normal adult humans. This new method of delivery can revolutionize the treatment of Alzheimer's disease, stroke, and other brain disorders.